3,4&#39;-dideoxymycaminosltylonolide derivative and process for producing the same

ABSTRACT

A compound of the following formula is provided: ##STR1## wherein A represents a carbonyl group which may be protected; B represents an aldehyde group which may be protected; R 1  represents a hydroxyl group which may be protected; R 2  represents a hydrogen atom or acyl group; W represents a hydrogen atom, hydroxyl group, lower alkanoyloxy group or substituted sulfonyloxy group; Y represents a hydrogen atom, halogen atom, hydroxyl group or substituted sulfonyloxy group; and broken line &#34;-------&#34; represents a double bond or single bond. This compound is useful for producing 3,4&#39;-dideoxymycaminosyltylonolide useful as an antimicrobial agent.

TECHNICAL FIELD

The present invention relates to an intermediate useful for producing3,4'-dideoxymycaminosyltylonolide which is an antimicrobial substancehaving an excellent effect of protection from an infection, and aprocess for producing the same.

BACKGROUND ART

3,4'-Dideoxymycaminosyltylonolide and salts thereof exhibit anantimicrobial activity on Gram-positive and Gram-negativemicroorganisms, and they are usable as antimicrobial agents havingparticularly excellent effect of protection from an infection [seeJapanese Patent Unexamined Published Application (hereinafter referredto as "J. P. KOKAI") No. Hei 2-275894].

3,4'-Dideoxymycaminosyltylonolide can be produced by protectingfunctional groups of mycaminosyltylonolide which is an acid hydrolyzateof tylosin, then converting the hydroxyl groups at the 3-position and4'-position into deoxy groups and further removing the protectinggroups. For converting the hydroxyl group at the 4'-position into deoxygroup, a known process can be employed, such as a process wherein thehydroxyl groups at the 3-position and 4'-position are sulfonylated, thenthe hydroxyl group at the 4' position is halogenated by a methoddescribed in J. Antibiotics 34, pages 1374 to 1376 or J. P. KOKAI No.Hei 2-191295 and the halogen atom is removed by reduction withtributyltin hydride. The sulfonic acid can be eliminated from thehydroxyl group at the 3-position to form a double bond, which iscatalytically reduced to form the deoxy compound.

However, the above-described process for producing3,4'-dideoxymycaminosyltylonolide has a defect in that the yield of theintended product is low, since the conversion of the hydroxy groups atthe 3-position and 4'-position into deoxy group necessitates thefollowing steps: sulfonylating both hydroxyl groups; halogenating thehydroxyl group at the 4'-position and removing the halogen atom byreduction with tributyltin hydride; and forming double bond elimitatingsulfonyloxy group at the 3-position and reducing the double bond. Inaddition, tributyltin hydride used for forming the deoxy group at the4'-position has an offensive odor to make the purification of thereaction product difficult. Thus problems are posed when this reactionis employed on an industrial scale.

Therefore, the object of the present invention is to provide a usefulintermediate for producing 3,4'-dideoxymycaminosyltylonolide. Anotherobject of the present invention is to provide a process for efficientlyconverting the groups at the 3- and 4'-positions into deoxy group.

DISCLOSURE OF THE INVENTION

As a useful intermediate for producing3,4'-dideoxymycaminosyltylonolide, the present invention provides acompound of the following formula (I): ##STR2## wherein A represents acarbonyl group which may be protected; B represents an aldehyde groupwhich may be protected; R^(x) represents a hydroxyl group which may beprotected; R² represents a hydrogen atom or acyl group; W represents ahydrogen atom, hydroxyl group, lower alkanoyloxy group or substitutedsulfonyloxy group; Y represents a hydrogen atom, halogen atom, hydroxylgroup or substituted sulfonyloxy group; and broken line "-------"represents a double bond or single bond.

Examples of the compounds of the present invention represented by theformula (I) include the following ones:

(a) compounds of the formula (I) wherein A, B and R² are as definedabove, R¹ represents a group Of the following formula: ##STR3## (Z beingCHR⁴ or C═O, and R⁴ being a hydroxyl group which may be protected), Wrepresents a hydrogen atom or substituted sulfonyloxy group, Yrepresents a hydrogen atom, halogen atom or substituted sulfonyloxygroup, and broken line "-------" represents a single bond;

(b) compounds of the formula (I) wherein A, B and R² are as definedabove, R¹ represents a group of the following formula: ##STR4## (Z beingCHR⁴ or C═O, and R⁴ being a hydroxyl group which may be protected), Wrepresents a hydrogen atom or lower alkanoyloxy group, Y represents ahalogen atom, hydroxyl group or substituted sulfonyloxy group, andbroken line "-------" represents a double bond when W is hydrogen atomand a single bond when W is a lower alkanoyloxy group; and

(c) compounds of the formula (I) wherein A, B and R² are as definedabove, R¹ represents a hydroxyl group which may be protected [with theproviso that R¹ cannot be a group of the following formula: ##STR5## (Zbeing CHR⁴ or C═O, and R⁴ being a hydroxyl group which may beprotected)], W represents a hydrogen atom or lower alkanoyloxy group, Yrepresents a halogen atom, hydroxyl group or substituted sulfonyloxygroup, and broken line "-------" represents a double bond when W ishydrogen atom and a single bond when W is a lower alkanoyloxy group.

In another embodiment, the present invention provides:

(d) a process for producing a compound 6f the formula (I) wherein A, B,R¹ and R² are as defined above, W and Y each represent a hydrogen atomand broken line "-------" represents a single bond by reducing acompound of the formula (I) wherein A, B, R¹ and R² are as definedabove, W represents a substituted sulfonyloxy group, Y represents ahalogen atom and broken line "-------" represents a single bond under analkaline condition, and

(e) a process for producing a compound of the formula (I), whichcomprises steps of reacting a compound of the formula (I) wherein A, B,R¹ and R² are as defined above, W and Y each represent a hydroxyl groupand broken line "-------" represents a single bond with a sulfonylatingagent to form a compound of the above formula (I) wherein A, B, R¹ andR² are as defined above, W and Y each represent a substitutedsulfonyloxy group and broken line "-------" represents a single bond;reacting the resultant compound with a halogenating agent to form acompound of the formula (I) wherein A, B, R¹ and R² are as definedabove, W represents a substituted sulfonyloxy group, Y represents ahalogen atom and broken line "-------" represents a single bond; andreducing the resultant compound under an alkaline condition to form acompound of the formula (I) wherein A, B, R¹ and R² are as definedabove, W and Y each represent a hydrogen atom and broken line "-------"represents a single bond.

BEST MODE FOR CARRYING OUT THE INVENTION

In the formula (I) for the compound of the present invention, Arepresents a carbonyl group which may be protected, and B represents analdehyde group which may be protected. The protecting group for thecarbonyl and aldehyde groups may be any of those well known in the art.They include, for example, acetals (or thioacetals) and ketals (orthioketals) which may contain substituents such as methyl group; e.g.dimethylacetal (dimethylketal), diethylacetal (diethylketal),diethylthioacetal (diethylthioketal), ethyleneacetal (ethyleneketal) andpropyleneacetal (propyleneketal).

In the formula (I) of the compound of the present invention, R¹represents a hydroxyl group which may be protected. The protecting groupfor the hydroxyl group may be any of those well known in the art. Theyinclude, for example, alkylsilyl groups such as t-butyldimethylsilyl,dimethylhexylsilyl, trimethylsilyl, triethylsilyl and tri(t-butyl)silylgroups; trityl group; tetrahydropyranyl group; tetrahydrofuranyl group;allyl group; lower alkanoyl groups such as substituted and unsubstitutedacetyl groups; benzoyl group; benzyl group; methoxymethyl group; andbenzyloxycarbonyl group. The substituted acetyl groups include, forexample, halogen-substituted acetyl groups such as fluoroacetyl,difluoroacetyl, trifluoroacetyl, chloroacetyl, dichloroacetyl,trichloroacetyl, bromoacetyl and dibromoacetyl groups; and alkoxyacetylgroups such as methoxyacetyl, ethoxyacetyl and phenoxyacetyl groups.Mycinosyl group is also usable as the protecting group for the hydroxylgroup. The hydroxyl group of mycinosyl group may be protected with aprotecting group listed above for the hydroxyl group.

In the formula (I) for the compound of the present invention, R²represents a hydrogen atom or acyl group. The acyl groups include, forexample, lower alkanoyl groups, lower alkenoyl groups, aroyl groups andphenyl(lower)alkanoyl groups. The lower alkanoyl groups include, forexample, linear or branched alkanoyl groups having 1 to 6 carbon atoms.They include acyl groups such as formyl, acetyl, propionyl, butyryl,isobutyryl, valeryl, isovaleryl, pivaloyl and hexanoyl groups; aroylgroups such as benzoyl, toluoyl and xyloyl groups; and phenyl(lower)alkanoyl groups such as phenylacetyl, phenylpropionyl and phenylhexanoylgroups.

In the formula (I) for the compound of the present invention, Wrepresents a hydrogen atom, hydroxyl group, lower alkanoyloxy group orsubstituted sulfonyloxy group. The lower alkanoyloxy groups include, forexample, linear or branched alkanoyloxy groups having 1 to 6 carbonatoms. In particular, the alkanoyloxy groups include acetoxy andpropionyloxy groups, etc. The substituted sulfonyloxy group isrepresented by the formula: --OSO₂ R₃ wherein R³ represents, forexample, a lower alkyl group, trifluoromethyl group, 2-oxo-10-bornanylgroup, substituted or unsubstituted aryl group or substituted orunsubstituted aralkyl group. The lower alkyl groups include, forexample, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,pentyl, 1-methylbutyl, 2-methylbutyl and neopentyl groups. Thesubstituted or unsubstituted aryl groups include, for example, phenyl,p-methoxyphenyl, p-nitrophenyl, p-fluorophenyl, o,p-difluorophenyl,p-chlorophenyl, m-chlorophenyl, o-chlorophenyl, o,p-dichlorophenyl,p-bromophenyl, p-methylphenyl, m-methylphenyl, o,p-dimethylphenyl,m,p-dimethylphenyl and naphthyl groups. The substituted or unsubstitutedaralkyl groups include, for example, benzyl, p-nitrobenzyl,o,p-dinitrobenzyl, p-chlorobenzyl, m-chlorobenzyl, p-methylbenzyl,m-methylbenzyl, o-methylbenzyl, o,p-dimethylbenzyl, p-methoxybenzyl andp-fluorobenzyl groups.

In the formula (I) for the compound of the present invention, Yrepresents a hydrogen atom, halogen atom, hydroxyl group or substitutedsulfonyloxy group. The halogen atom may be any of chlorine, bromine andiodine atoms. The substituted sulfonyloxy groups are those describedabove. When Y represents a halogen atom, hydroxyl group or substitutedsulfonyloxy group, the configuration of the substituent Y is such thatit is at either cis- or trans-position to the adjacent dimethylaminogroup [--N(CH₃)₂ ]. Therefore, the compound of the general formula (I)include a geometrical isomer in which the configuration of thesubstituent Y is such that it is at either cis- or trans-position to theadjacent dimethylamino group [--N(CH₃)₂ ] or a mixture of the isomers inany proportion. The broken line "-------" represents a double bond or asingle bond.

A preferred embodiment of the present invention is a compound (a) of theformula (I) wherein A, B and R² are as defined above, R¹ represents agroup of the following formula: ##STR6## (Z being CHR⁴ or C═O, and R⁴being a hydroxyl group which may be protected), W represents a hydrogenatom or substituted sulfonyloxy group, Y represents a hydrogen atom,halogen atom or substituted sulfonyloxy group, and broken line "-------"represents a single bond;

Another preferred embodiement of the present invention is a compound (b)of the formula (I) wherein A, B and R² are as defined above, R¹represents a group of the following formula: ##STR7## (Z being CHR⁴ orC═O, and R⁴ being a hydroxyl group which may be protected), W representsa hydrogen atom or lower alkanoyloxy group, Y represents a halogen atom,hydroxyl group or substituted sulfonyloxy group, and broken line"-------" represents a double bond when W is hydrogen atom and a singlebond when W is a lower alkanoyloxy group.

Furthermore, another preferred embodiment of the present invention is acompound (c) of the formula (I) wherein A, B and R² are as definedabove, R¹ represents a hydroxyl group which may be protected [with theproviso that R¹ cannot be a group of the following formula: ##STR8## (Zbeing CHR⁴ or C═O, and R⁴ being a hydroxyl group which may beprotected)], W represents a hydrogen atom or lower alkanoyloxy group, Yrepresents a halogen atom, hydroxyl group or substituted sulfonyloxygroup, and broken line "-------" represents a double bond when W ishydrogen atom and a single bond when W is a lower alkanoyloxy group.

In the above-described compounds (a), (b) and (c), Z represents CHR⁴ orC═O, and R⁴ represents a hydroxyl group which may be protected. Thehydroxyl group which may be protected may be selected from among theabove-mentioned ones excluding hydroxyl group protected with mycinosylgroup.

The compounds of the present invention can be produced by, for example,a scheme which will be given below. However, the compounds of thepresent invention and the processes for producing them are not limitedto the compounds and processes described in the schemes. The numbers ofthe compounds in the schemes correspond to Examples given in thisspecification.

Abbreviation:

Ac: acetyl

Bes: benzylsulfonyl

DM: desmycosin

DMT: demycinosyltylosin

Do: deoxy

ED: ethylenedioxy

iVal: isovaleryl

Ms: methanesulfonyl

MT: mycaminosyltylonolide

TBDS: t-butyldimethylsilyl

TMS: trimethylsilyl

EDMT: mycaminosyltylonolide 9,20-bis(ethyleneacetal)

TBDS-EDMT: 23-O-t-butyldimethylsilylmycaminosyltylonolide9,20-bis(ethyleneacetal)

3,4'-Bes-TBDS-EDMT:3,4'-di-O-benzylsulfonyl-23-O-t-butyldimethylsilylmycaminosyltylonolide9,20-bis(ethyleneacetal)

3-Bes-4'-I-TBDS-EDMT:3-O-benzylsulfonyl-23-O-t-butyldimethylsilyl-4'-deoxy-4'-iodomycaminosyltylonolide9,20-bis(ethyleneacetal)

3,4'-Do-TBDS-EDMT:23-O-t-butyldimethylsilyl-3,4'-dideoxymycaminosyltylonolide9,20-bis(ethyleneacetal)

3,4'-Do-MT: 3,4'-dideoxymycaminosyltylonolide

2'-Ac-EDDM: 2'-O-acetyl desmycosin 9,20-bis(ethyleneacetal)

2'-Ac-4"-TMS-EDDM: 2'-O-acetyl-4"-O-trimethylsilyl desmycosin9,20-bis(ethyleneacetal),

2',4"-Ac-EDDM: 2',4"-di-O-acetyl desmycosin 9,20-bis(ethyleneacetal),

2'-Ac-3,4'-Ms-4"-TMS-EDDM:2'-O-acetyl-3,4'-di-O-methanesulfonyl-4"-O-trimethylsilyl desmycosin9,20-bis(ethyleneacetal),

2'-Ac-4'-I-3Ms-4"-TMS-EDDM:2'-O-acetyl-4'-deoxy-4'-iodo-3-O-methanesulfonyl -4"-O-trimethylsilyldesmycosin 9,20-bis(ethyleneacetal),

3,4'-Do-EDDM: 3,4'-dideoxy desmycosin 9,20-bis(ethyleneacetal),

2'-Ac-3,4'-Do-EDDM: 2'-O-acetyl-3,4'-dideoxy desmycosin9,20-bis(ethyleneacetal),

2'-Ac-3,4'-Do-4"-Oxo-EDDM: 2'-O-acetyl-3,4'-dideoxy-4"-oxo desmycosin9,20-bis(ethyleneacetal),

3,4'-Do-EDMT: 3,4'-dideoxymycaminosyltylonolide9,20-bis(ethyleneacetal),

3,2',4"-Ac-EDDM: 3,2',4"-tri-O-acetyl desmycosin9,20-bis(ethyleneacetal),

2',4"-Ac-Δ² -EDDM: 2',4"-di-O-acetyl-2,3-dehydro-3-deox y desmycosin9,20-bis(ethyleneacetal),

2',4"-Ac-Δ² -4'-Ms-EDDM:2',4"-di-O-acetyl-2,3-dehydro-3-deoxy-4'-O-methanesulfonyl desmycosin9,20-bis(ethyleneacetal),

2',4"-Ac-Δ² -4'-I-EDDM: 2',4"-O-acetyl-2,3-dehydro-3,4'-dideoxy-4'-iododesmycosin 9,20-bis(ethyleneacetal),

3,2',4"-Ac-4'-Ms-EDDM: 3,2',4"-tri-O-acetyl-4'-O-methanesulfonyldesmycosin 9,20-bis(ethyleneacetal),

3,2',4"-Ac-4'-I-EDDM: 3,2',4"-tri-O-acetyl-4'-deoxy-4'-iodo desmycosin9,20-bis(ethyleneacetal),

3,2'-Ac-4"-iVal-DMT: 3,2'-di-O-acetyl-4"-O-isovaleryldemycinosyltylosin,

3,2'-Ac-MT: 3,2'-di-O-acetylmycaminosyltylonolide,

3,2'-Ac-EDMT: 3,2'-di-O-acetylmycaminosyltylonolide9,20-bis(ethyleneacetal)

3,2'-Ac-TBDS-EDMT:3,2'-di-O-acetyl-23-O-t-butyldimethylsilylmycaminosyltylonolide9,20-bis(ethyleneacetal)

2'-Ac-Δ² -TBDS-EDMT: 2-O-acetyl-23-O-t-butyldimethylsilyl-2,3-dehydro-3-deoxymycaminosyltylonolide, 9,20-bis(ethyleneacetal)

2'-Ac-Δ² -4'-Ms-TBDS-EDMT:2'-O-acetyl-23-O-t-butyldimethylsilyl-2,3-dehydro-3-deoxy-4'-O-methanesulfonylmycaminosyltylonolide9,20-bis(ethyleneacetal)

2'-Ac-Δ² -4'-I-TBDS-EDMT:2'-O-acetyl-23-O-t-butyldimethylsilyl-2,3-dehydro-3,4'-dideoxy-4'-iodomycaminosyltylonolide 9,20-bis(ethyleneacetal)

3,2'-Ac-4'-Ms-TBDS-EDMT:3,2'-di-O-acetyl-23-O-t-butyldimethylsilyl-4'-O-methanesulfonylmycaminosyltylonolide9,20-bis(ethyleneacetal), and

3,2'-Ac-4'-I-TBDS-EDMT:3,2'-di-O-acetyl-23-O-t-butyldimethylsilyl-3,4'-dideoxy-4'-iodomycaminosyltylonolide9,20bis(ethyleneacetal). ##STR9##

The present invention provides:

(d) a process for producing a compound of the above formula (I) whereinA, B, R¹ and R² are as defined above, W and Y each represent a hydrogenatom and the broken line "-------" represents a single bond by reducinga compound of the formula (I) wherein A, B, R¹ and R² are as definedabove, W represents a substituted sulfonyloxy group, Y represents ahalogen atom and the broken line "-------" represents a single bondunder an alkaline condition; and

(e) a process for producing a compound of the above formula (I) whereinA, B, R¹ and R² are as defined above, W and Y each represent a hydrogenatom and the broken line "-------" represents a single bond, whichcomprises steps of reacting a compound of the formula (I) wherein A, B,R¹ and R² are as defined above, W and Y each represent a hydroxyl groupand the broken line "-------" represents a single bond with asulfonylating agent to form a compound of the above formula (I) whereinA, B, R¹ and R² are as defined above, W and Y each represent asubstituted sulfonyloxy group and the broken line "-------" represents asingle bond; reacting the compound thus obtained with a halogenatingagent to form a compound of the above formula (I) wherein A, B, R¹ andR² are as defined above, W represents a substituted sulfonyloxy group, Yrepresents a halogen atom and the broken line "-------" represents asingle bond; and reducing the compound thus obtained under an alkalinecondition to obtain a compound of the above formula (I) wherein A, B, R¹and R² are as defined above, W and Y each represent a hydrogen atom andthe broken line "-------" represents a single bond.

The compounds of the above-mentioned formula wherein A, B, R¹ and R² areas defined above, W and Y each represent a hydrogen atom and the brokenline "-------" represents a single bond, thus produced by theabove-described processes, are also preferred ones in the presentinvention.

The mycaminosyltylonolide derivatives shown in the above productionschemes 1 and 2 can be produced from easily available tylosin. Forexample, they can be produced by hydrolyzing tylosin with an acid andthen protecting, if necessary, hydroxyl, aldehyde and carbonyl groups ofthe obtained mycaminosyltylonolide with the abovedescribed protectinggroup. Another process is disclosed in Journal of Antibiotics (35, 661,1982) wherein tylosin is treated with an acid anhydride to obtain2'-o-acyltylosin, which is then hydrolyzed with an acid andsimultaneously or therafter protected with the protecting group toobtain a mycaminosyltylonolide having a mycinosyl group.

By reacting the thus-obtained mycaminosyltylonolide derivative with asulfonylating agent, the hydroxyl groups at the 3-position and4'-position are converted into the substituted sulfonyloxy groups toform the corresponding compound. The sulfonylating agents are, forexample, halides and anhydrides. The sulfonylating agent for giving adesired substituted sulfcnyloxy group can be easily selected by thoseskilled in the art. Examples of the sulfonylating agents includemethanesulfonyl chloride, methanesulfonic anhydride, ethanesulfonylchloride, propanesulfonyl chloride, butanesulfonyl chloride,pentanesulfonyl chloride, trifluoromethanesulfonyl chloride,trifluoromethanesulfonic anhydride, benzenesulfonyl chloride,pmethoxyphenylsulfonyl chloride, p-nitrophenylsulfonyl chloride,p-fluorophenylsulfonyl chloride, o,p-difluorophenylsulfonyl chloride,p-chlorophenylsulfonyl fluorophenylsulfonylchloride,m-chlorophenylsulfonyl chloride, o-chlorophenylsulfonyl chloride,o,p-dichlorophenylsulfonyl chloride, p-bromophenylsulfonyl chloride,p-methylphenylsulfonyl chloride, p-methylphenylsuflonic anhydride,m-methylphenylsulfonyl chloride, o,p-dimethylphenylsulfonyl chloride,m,p-dimethylphenylsulfonyl chloride, naphthylsulfonyl chloride,camphorsulfonyl chloride, benzylsulfonyl chloride, p-nitrobenzylsulfonylchloride, o,p-dinitrobenzylsulfonyl chloride, p-chlorobenzylsulfonylchloride, m-chlorobenzylsulfonyl chloride, p-methylbenzylsulfonylchloride, m-methylbenzylsulfonyl chloride, o-methylbenzylsulfonylchloride, o,p-dimethylbenzylsulfonyl chloride, p-methoxybenzylsulfonylchloride and p-fluorobenzylsulfonyl chloride. The sulfonylating agentsare not limited to those listed above.

The sulfonylation reaction with the above-described sulfonylating agentis conducted usually in an organic solvent at a temperature ranging from-40° to +50° C. The solvents usable herein include, for example,acetonitrile, acetone, methyl ethyl ketone, dimethyl sulfoxide, dioxaneand toluene. It is also possible to use pyridine,4-dimethylaminopyridine, triethylamine or the like as the basic catalystand/or solvent.

The compound produced by selectively introducing a halogen into the4'-position can be obtained by reacting the mycaminosyltylonolidederivative in which the hydroxyl groups at the 3-position and4'-position have been converted into the substituted sulfonyloxy groupwith a halogenating agent such as sodium iodide, potassium iodide,lithium bromide, tetrabutylammonium bromide or tetrabutylammoniumchloride in an inert solvent such as acetone, methyl ethyl ketone,dimethoxyethane or dimethylformamide. The halogenation reaction isconducted usually at room temperature to 100° C. depending on the kindof the substituted sulfonyloxy group. Depending on the halogenationconditions, a compound having a double bond at 2- and 3-positions or at3- and 4-positions is partially formed, which can be used as a startingcompound in the subsequent step.

By reducing the above-described compound having the substitutedsulfonyloxy group and halogen atom in place of the hydroxyl groups atthe 3-position and 4'-position under the alkaline condition, the groupsat the 3-position and 4'-position can be simultaneously replaced withhydrogen to form 3,4'-dideoxy derivative. This reaction can be conductedby, for example, a catalytic reduction in the presence of a catalyst ina solvent inert to the reaction. The bases usable for realizing thealkaline condition include, for example, sodium hydroxide, sodiumcarbonate, sodium hydrogencarbonate, potassium carbonate and potassiumhydrogencarbonate. Among them, potassium carbonate is preferred. Such abase is used usually in an amount of 1 to 5 mol per mol of the3-substituted sulfonyloxy-4'-halogen compound used as the substrate. Thecatalysts usable for the catalytic reduction include, for example,platinum, palladium and Raney nickel. Among them, Raney nickel ispreferred. The amount of the catalyst which varies depending on thevariety of the catalyst is usually 1/10 to 1/1 part by weight per partby weight of the compound used as the substrate. The inert solventsinclude, for example, methanol, ethanol and tetrahydrofuran. Thecatalytic reduction is conducted under cooling or at room temperature,preferably at a reaction temperature of -10° to +30° C. under a hydrogenpressure ranging from atmospheric pressure to 5 kg/cm². These conditionswhich vary depending on the starting compounds and the catalyst aresuitably selected by those skilled in the art.

The groups at the 3-position and 4'-position of the 3-substitutedsulfonyloxy-4'-halogen compound can be replaced with hydrogen at once bythe above-described reaction. Thus, a high yield of 3,4'-deoxy compoundcan be obtained in one step. By removing the protecting groups from the3,4'-deoxy compound by an ordinary method, it can be converted into3,4'-dideoxymycaminosyltylonolide or a salt thereof useful as anantimicrobial agent. The protecting group can be removed usually bytreatment with a mineral acid such as hydrochloric acid or sulfuric acidor with an organic acid such as acetic acid, trifluoroacetic acid ortrichloroacetic acid in the presence of water. The protecting group canbe removed also by treatment with an arylsulfonic acid such asp-toluenesulfonic acid or an alkylsulfonic acid such as methanesulfonicacid in a solvent such as dioxane, dimethylformamide, dimethyl sulfoxideor acetonitrile at room temperature or under heating. When theprotecting group for the hydroxyl group is mycinosyl group, this groupcan be oxidized to form a corresponding ketone, which is then treatedwith an acid or base.

Compounds of the formula (I) of the present invention wherein A, B andR² are as defined above, W represents a hydrogen atom, Y represents ahydroxyl group, R¹ represents a protected hydroxyl group and the brokenline "-------" represents a double bond (2',4"-di-O-acyl-Δ² -desmycosinbisacetal) can be produced by the process of the above production scheme3-1. By this process, 3-O-acetyltylosin easily available on the market(see Journal of Antibiotics 27, 542, 1979) is acylated to form2',4"'-di- or 2',4",4"'-tri-O-acyl-3-O-acetyltylosin by, for example, amethod described in Journal of Antibiotics 35, 661, 1982, then theresultant compound is treated with a dehydrating agent and an alcohol inthe presence of about 1.1 to 1.5 mol, per mol of the compound, of anacid catalyst in an inert solvent such as toluene at a temperature ofabout 5° to 80° C. to form a 9,20-bisacetal of2',4"-di-O-acyl-3-O-acetyl desmycosin, and finally the resultantcompound is treated with about 1.0 to 5.0 mol, per mol of the compound,of a base in an inert solvent such as dimethyl sulfoxide.

The alcohols usable in the above-described reaction include, forexample, methanol, ethanol, propanol, butanol, ethylene glycol,propanediol and 2,3-butanediol. Such an alcohol is used in an amount ofabout 5 to 20 mol, per mol of the starting compound. The dehydratingagents include, for example, ethyl orthoformate, methyl orthoformate,anhydrous calcium chloride, anhydrous sodium sulfate, anhydrousmagnesium sulfate and molecular sieves. The acid catalysts include, forexample. camphorsulfonic acid, benzenesulfonic acid, toluenesulfonicacid, methanesulfonic acid, sulfuric acid and Amberlyst 15. The basesusable in the acetic acid-removing step include, for example, sodiumhydride, tert-butoxypotassium, magnesium methoxide, magnesium ethoxide,sodium methoxide, sodium ethoxide, 1,8-diazabicyclo[5.4.0]-7-undeceneand 1,5-diazabicyclo[4.3.0]-5-nonene.

The above-described compound can be converted into a compound of theformula [I] wherein Y represents a substituted sulfonyloxy group byreacting it with the above-described sulfonylating agent in the presenceof an organic base such as pyridine, collidine, lutidine, triethylamineor diisopropylethylamine in an inert solvent at a temperature of about-25° to +25° C. It is also possible to obtain a compound of the aboveformula [I] wherein Y represents a halogen atom by reacting the compoundof the above formula [I] wherein Y represents a substituted sulfonyloxygroup with about 1 to 5 mol, per mol of the compound, a halogenatingagent in a solvent such as acetone, methyl ethyl ketone,dimethoxyethane, acetonitrile, dimethyl sulfoxide or dimethylformamideat a temperature of about 50° to 100° C.

The compound of the formula (I) of the present invention wherein A, Band R² are as defined above, W represents a hydrogen atom, Y representsa halogen atom, R¹ represents a protected hydroxyl group and the brokenline "-------" represents a double bond can be converted into acorresponding 3,4'-deoxycompound by the hydrogen replacement at the3-position and 4'-position at once by, for example, catalytic reductionunder alkaline condition in the same manner as those described above.Then the protecting groups are removed by an ordinary method to obtain3,4'-dideoxymycaminosyltylonolide or a salt thereof useful as theantimicrobial agent.

The compound of the present invention can be produced from3-O-acetyltylosin according to, for example, the production scheme 3-2.For example, 3-O-acetyltylosin is acylated by a method described inJournal of Antibiotics (35, 661, 1982) to form 2',4"'-di- or2',4",4"'-tri-O-acyl-3-O-acetyltylosin and then the resultant compoundis converted into an acetal with a dehydrating agent, an alcohol and anacid catalyst to obtain 9,20-bisacetal of 2',4"-di-O-acyl-3-O-acetyldesmycosin.

In the acetalization reaction, an alcohol capable of forming an intendedacetal or ketal is used either singly or in combination with an inertsolvent. The alcohols include methanol, ethanol, propanol, butanol,ethylene glycolo, propanediol, 2,3-butanediol, etc. The alcohol is usedin an amount of 5 to 20 mol per mol of the macrolide compound. The inertsolvents usable herein include toluene, benzene, ethyl acetate,chloroform, dichloromethane, etc. The dehydrating agents include ethylorthoformate as well as methyl orthoformate, anhydrous calcium chloride,anhydrous sodium sulfate, anhydrous magnesium sulfate, molecular sieves,etc. The acid catalysts include p-toluenesulfonic acid as well asbenzenesulfonic acid, camphorsulfonic acid, methanesulfonic acid,sulfuric acid, Amberlyst 15, etc. The acid catalyst is preferably usedin an amount of 1.1 to 1.5 mol per mol of the starting compound. Thereaction temperature is 5° to 80° C., preferably 20° to 70° C. andparticularly room temperature to 50° C.

The compound thus obtained can be converted into a compound sulfonylatedat the 4'-position by reacting it with a sulfonylating agent under theabove-described reaction conditions. The compound thus sulfonylated atthe 4'-position is relatively unstable and, therefore, it is preferablysubjected to the subsequent reaction without isolation or purification.This compound can be converted into a compound halogenated at the4'-position by halogenation under the above-described conditions.

This compound can be converted into2',4"-di-O-acyl-2,3-dehydro-3,4'-dideoxy-4'-halo-desmycosin bisacetal byremoving acetic acid at the 2- and 3-positions as follows: the compoundhalogenated at the 4'-position is dissolved in an inert solvent such astoluene, diethyl ether, tetrahydrofuran, dimethoxyethane, dioxane,dimethyl sulfoxide or dimethylformamide, and then treated with a basesuch as sodium hydride, tert-butoxypotassium, maqnesium methoxide,magnesium ethoxide, sodium methoxide, sodium ethoxide,1,8-diazabicyclo[5.4.0]-7-undecene or 1,5-diazabicyclo[4.3.0]-5-nonene.This reaction is conducted at, for example, a temperature of -10° to 80°C. The base is used in an amount of 1.0 to 5.0 mol, preferably 1.0 to3.0 mol, per mol of the starting compound.

The compound thus obtained is dissolved in, for example, methanol orethanol and catalytically reduced in the presence of a catalyst such asRaney nickel and a base under a hydrogen pressure ranging fromatmospheric pressure to about 4.0 kg/cm² according to the productionscheme 3--3 to obtain 3,4'-dideoxy desmycosin bisacetal. This reactioncan be conducted at, for example, room temperature, and 1 to 3 mol of abase such as sodium hydrogencarbonate, potassium hydrogencarbonate,potassium carbonate or sodium carbonate is used per mol of the macrolidecompound. When Raney nickel is used as the catalyst, the variety thereofis not particularly limited. For example, NDT-65 or NDHT-90 (a productof Kawaken Fine Chemicals, Co., Ltd.) is usable. It is preferred toconduct the reaction in the presence of 0.1 to 1.0 part by weight of thecatalyst per part by weight of the macrolide compound. The resultantcompounnd is treated with about 1.1 equivalent of an acid anhydride tointroduce an acyl group into the 2'-position, thereby obtaining acorresponding 2'-O-acyl-3,4'-dideoxy desmycosin bisacetal.

This compund is treated with an oxidizing agent to oxidize the hydroxylgroup at the 4"-position and to obtain a high yield of the intendedcompound. The oxidizing agents include, for example, combinations ofdimethyl sulfoxide/acetic anhydride, dimethyl sulfoxide/trifluoroaceticanhydride, dimethylsulfoxide/dicyclohexylcarbodiimide/pyridine/trifluoroacetic acid,dimethyl sulfide/N-chlorosuccinimide/triethylamine andtetrahydrothiophene/N-chlorosuccinimide/triethylamine as well asordinary oxidizing agents having a secondary hydroxyl group. Theoxidizing agent is used in an amount of about 2 to 10 mol per mol of thestarting compound. Although the reaction conditions vary depending onthe variety of the oxidizing agent, the reaction temperature ranges -20°C. to 80° C.

The mycinose part can be easily removed by treating the 4"-oxo compoundobtained by the above-described process with a base in an inert solvent.For example, the 4"-oxo compound is treated with a base such as sodiumhydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,ammonium acetate, 1,8-diazabicyclo[5.4.0]-7-undecene or1,5-diazabicyclo[4.3.0]-5-nonene in an organic solvent such as methanol,ethanol, dioxane, tetrahydrofuran, dimethoxyethane, dimethylformamide ora mixture of two or more of them or a mixture of such an organic solventwith water. Though the reaction temperature ranges from 0° to 100° C., atemperature below room temperature is preferred.

The acetyl group at the 2'-position can be removed by an alcoholysisreaction in a solvent such as methanol or ethanol prior to themycinose-removing reaction or, alternatively, by the alcholysis reactionafter the mycinose-removing reaction. 3,4'-dideoxymycaminosyltylonolidebisacetal thus obtained is dissolved in an organic solvent such astetrahydrofuran or dioxane and then treated with dilute hydrochloricacid to conduct the deacetalization (deketalization), thereby obtaining3,4'-dideoxymycaminosyltylonolide.

According to the production scheme 4-1, a3-O-acetyl-4"-O-isovaleryldemycinosyltylosin (a compound described inJ.P. KOKOKU No. Sho 60-16960) can be converted into a corresponding2'-O-acyl-3-O-acetyl-4"-O -isovaleryldemycinosyltylosin by treating itwith an acid anhydride selected from various ones as described in, forexample, Journal of Antibiotics (35, 661, 1982). When the resultantcompound is hydrolyzed under an acid condition realized in, for example,an aqueous solution of sulfuric acid, hydrochloric acid or phosphoricacid at -10° to 100° C., preferably 10° to 60° C., a corresponding2'-O-acyl-3-O-acetylmycaminosyltylonolide is obtained. Further, thiscompound can be converted into 9,20-bisacetal of the2'-O-acyl-3-O-acetylmycaminosyltylonolide by acetalizing it with adehydrating agent, alcohol and acid catalyst under the above-describedreaction conditions. On the other hand, when the2'-O-acyl-3-O-acetyl-4"-O-isovaleryldemycinosyltylosin is subjected tothe acetalization reaction under the above-described reactionconditions, acetalization and hydrolysis of the terminal saccharideoccur at the same time to obtain 9,20-bisacetal of the2'-O-acyl-3-O-acetylmycaminosyltylonolide in one step.

When 9,20-bisacetal of the 2'-O-acyl-3-O-acetylmycaminosyltylonolidethus obtained is reacted with, for example, a reactive silyl compound inthe presence of a base, a corresponding compound having protectedhydroxyl group at the 23-position can be obtained. The solvents usablefor this reaction include dimethylformamide as well as acetone,acetonitrile, tetrahydrofuran, toluene and chloroform. The basiccatalysts include inorganic and organic bases such as sodium carbonate,potassium carbonate, sodium hydrogencarbonate, pyridine, lutidine,picoline, triethylamine, diisopropylethylamine and imidazole. Thereactive silyl compounds usable herein include trimethylsilyl chloride,triethylsilyl chloride, tripropylsilyl chloride, t-butyldimethylsilylchloride, dimethoxymethylsilyl chloride, dimethylphenylsilyl chloride,etc. The reaction can be conducted at -10° to 50 ° C.

The compound having the protected hydroxyl group at the 23-position isdissolved in an inert solvent such as toluene, diethyl ether,tetrahydrofuran, dimethoxyethane, dioxane, dimethyl sulfoxide ordimethylformamide, and then reacted with a base such as sodium hydride,t-butoxypotassium, magnesium methoxide, magnesium ethoxide, sodiummethoxide, sodium ethoxide, 1,8-diazabicyclo[5.4.0]-7-undecene or1,5diazabicyclo[4.3.0]-5-nonene at -10° to 80° C. to obtain acorresponding 2'-O-acyl-2,3-dehydro-mycaminosyltylonolide bisacetalwhich is a 2,3-deacetylation product. The base is used in an amount of1.0 to 5.0 mol, preferably 1.0 to 3.0 mol, per mol of the macrolidecompound. A compound sulfonylated at the 4'-position can be producedfrom this compound by reacting it with the above-described sulfonylatingagent in the presence of a base such as pyridine, collidine, lutidine,triethylamine or diisopropylethylamine in an inert solvent such asacetone, methyl ethyl ketone, dimethoxyethane, acetonitrile, toluene,dimethyl sulfoxide or dimethylformamide at -25° to 25° C.

Although the compound thus sulfonylated at the 4'-position can beisolated and purified prior to the subsequent reaction, it is preferablysubjected to the halogenation reaction at the 4'-position thereofwithout the isolation, since this compound is relatively unstable. Bythe halogenation reaction conducted under the abovedescribed reactionconditions, the compound halogenated at the 4'-position, i.e.2'-O-acyl-2,3-dehydro-3,4'-dideoxy-4'-halomycaminosyltylonolidebisacetal, can be obtained.

According to the production scheme 4-2, the halogenated compound can beobtained also by protecting the hydroxyl group at the 23-position of9,20-bisacetal of the 2'-O-acyl-3-O-acetylmycaminosyltylonolide, thensulfonylating this compound at the 4'-position thereof under theabove-described reaction conditions, halogenating the resultant compoundunder the above-described reaction conditions, and deacylating it underthe above-described reaction conditions. Although the compoundsulfonylted at the 4'-position can be isolated and purified prior to thesubsequent reaction, it is preferably subjected to the subsequentreaction without the isolation, since the compound itself is relativelyunstable.

When the 2'-O-acyl-2,3-dehydro-3,4'-dideoxy-4'-halomycaminosyltylonolidebisacetal produced as described above is dissolved in, for example,methanol or ethanol and catalytically reduced in the presence of acatalyst such as a Raney nickel and a base under a hydrogen pressureranging from atmospheric pressure to about 4.0 kg/cm² under theabove-described reaction conditions according to the production scheme4-3, a corresponding 3,4'-dideoxymycaminosyltylonolide bisacetal isobtained. 3,4'-dideoxymycaminosyltylonolide can be produced bydissolving this compound in an organic solvent such as tetrahydrofuran,dioxane or acetone, and then treating it with dilute hydrochloric acidto conduct both deacetalization and removal of the protecting group atthe 23-position.

EXAMPLES

The following Examples will further illustrate the present invention,which by no means limit the present invention.

Example 13,4'-Di-O-benzylsulfonyl-23-O-t-butyldimethylsilyl-mycaminosyltylonolide9,20-bis(ethyleneacetal)

1.00 g (1.25 mmol) of 23-O-t-butyldimethylsilylmycaminosyltylonolide9,20-bis(ethylneacetal) was dissolved in 20 ml of anhydrous pyridine.After cooling to -40° C., 0.67 g (3.51 mmol) of benzylsulfonyl chloridewas added to the solution under stirring, and the reaction was conductedat -20° C. for 3 h. The reaction was confirmed by TLC, and terminated byaddition of 0.67 ml of water. The temperature was returned to roomtemperature. Water was added to the reaction liquid and, one hour after,the reaction liquid was concentrated under reduced pressure. Afterextraction with chloroform, the chloroform layer was washed withsaturated aqueous sodium hydrogencarbonate solution and then withsaturated aqueous common salt solution. After dehydration over magnesiumsulfate followed by filtration, the filtrate was concentrated to obtain1.38 g (quantitative) of crude3,4'-di-O-benzylsulfonyl-23-O-t-butyldimethylsilyl-mycaminosyltylonolide9,20-bis(ethyleneacetal) in the form of a light yellow solid foam.

Example 23-O-Benzylsulfonyl-23-O-t-butyldimethylsilyl-4'-deoxy-4,-iodomycaminosyltylonolide9,20-bis(ethyleneacetal):

415 mg (0.375 mmol) of the crude compound obtained in Example 1 wasdissolved in 6.2 ml of anhydrous methyl ethyl ketone. After purging withnitrogen, 84 mg (0.560 mmol) of sodium iodide was added to the solution,and the resultant mixture was stirred under heating at 80° C. 30 minafter, the reaction liquid was returned to room temperature andfiltered. The filter cake was washed with acetone. The filtrate and thewash solution were combined together and concentrated. The concentratewas extracted with chloroform, washed successively with saturatedaqueous sodium hydrogencarbonate solution, 10% sodium thiosulfate andsaturated aqueous common salt solution, and then dehydrated overmagnesium sulfate. After filtration followed by concentration of thefiltrate, 410 mg of a light yellow syrup was obtained. The syrup waspurified by silica gel column chromatography to obtain 300 mg (yield:75%) of3-O-benzylsulfonyl-23-O-t-butyldimethylsilyl-4'-deoxy-4'-iodo-mycaminosyltlonolide9,20bis(ethyleneacetal) in the form of a colorless solid.

Specific rotation [α]²⁷ _(D) -70° (Cl, CHCl₃)

    ______________________________________                                        Elementary analysis for C.sub.48 H.sub.78 NO.sub.13 ISSi:                               C    H          N      I (%)                                        ______________________________________                                        Found       54.09  7.27       1.08 11.95                                      Calculated  54.17  7.39       1.32 11.92                                      ______________________________________                                         FAB-MS: 1064 (M + H).sup.                                                

Example 3 3-O-t-Butyldimethylsilyl-3,4'-dideoxymycaminosyltylonolide9,20bis(ethyleneacetal)

296 mg (0.278 mmol) of the compound obtained in Example 2 was dissolvedin 6 ml of methanol. 0.5 ml of Raney nickel was added to the solution.After purging with argon followed by addition of 116 mg (0.835 mmol) ofpotassium carbonate, hydrogen was blown thereinto for 3 h. Afterconfirmation of the completion of the reaction by HPLC, the reactionliquid was filtered. After concentration of the filtrate followed byextraction with chloroform, the extract was washed with 1M aqueouspotassium carbonate solution and then with saturated aqueous sommon saltsolution. After dehydration over magnesium sulfate followed byfiltration, the filtrate was concentrated to obtain 204 mg (95%) of acrude compound in the form of a colorless solid foam. The solid productwas purifed by silica gel column chromatography to obtain 186 mg of23-O-t-butyldimethylsilyl-3,4'-dideoxymycaminosyltylonolide9,20-bis(ethyleneacetal) in the form of a colorless solid foam (yield:87%).

¹ H--NMR and mass spectrum of this product coincided with those of astandard sample synthesized by another route.

NMR(CDCl₃, TMS internal standard)

ε 0.88 (9H,s,t-butyl of, t-butyldimethylsylyl) 1.02(3H,d,H-21),1.24(3H,d,H-6'), 1.74(3H,s,H-22) 2.29(6H,s,N(CH₃)₂ -3'),4.28(1H,d,H-1'), 5.37(1H,d,H-13), 5.61(1H,d,H-10), 6.39(1H,d,H-11)

FAB-MS: 768 (M+H)⁺

Example 4 2'-O-Acetyl desmycosin 9,20-bis(ethyleneacetal)

23.7 g of 2'-O-acetyltylosin was suspended in 100 ml of toluene. 12.36 g(83.5 mmol) of ethyl orthoformate, 12.95 g (208.8 mmol) of ethyleneglycol and 6.30 g (27.1 mmol) of camphorsulfonic acid were added to theresultant suspension to obtain a homogeneous solution. The solution wasstirred at 50° C. for 2 h. Then the reaction solution was washed with100 ml of 5% aquous sodium hydrogencarbonate solution, 100 ml of waterand 10% aqueous common salt solution. The organic layer was dried overanhydrous sodium sulfate and then dried to solid under reduced pressureto obtain 20.20 g of the intended compound which was positive insulfuric acid color reaction at Rf 0.49 on silica gel TLC withtoluene/acetone (1/1) developer.

UV(MeOH)λ max: 235nm

IR(KBr) ν max: 3470,2975,2938,2882,1746,1236,1169,1084,961 cm⁻¹

NMR(CDCl₃): (only main peaks)

ε:0.78 (3H, bs, H-18), 0.93 (3H, t, J=7.3 Hz, H-17), 1.01 (3H, d, J=6.6Hz, H-Z1), 1.26 (3H, d, J=6.2 Hz, H-6"), 1.32 (3H, d, J=6.2 Hz, H-6'),1.70 (3H, s, H-22), 2.01 (3H, s, OCOCH₃ -2'), 2.39 (6H, s, N (CH₃)₂-3'), 3.05 (1H, t, J=9.5 Hz, H-4'), 3.18 (1H, bd, J=7. OHz, H-4"), 3.49(3H, s, OCH₃ -2"), 3.62 (3H, s, OCH₃ -3"), 4.55 (1H, d, J=8.1 Hz, H-1"),4.64 (1H, br, H-1'), 4.96 (1H, m, H-20), 4.96 (1H, m, H-15), 5.03 (1H,dd, J=10.6&7.7 Hz, H-2"), 5.42 (1H, d, J=10.6 Hz, H-13), 5.64 (1H, d,J=15.8 Hz, H-10), 6.37 (1H, d, J=15.8 Hz, H-11)

FAB-MS :902 (M+H)⁺

Example 5 Production of 2'-O-acetyl-4"-O-trimethylsilyl desmycosin9,20-bis(ethyleneacetal)

18.9 g (20.9 mmol) of 2'-O-acetyl desmycosin 9,20-bis(ethyleneacetal)was dissolved in 94 mol of toluene. 2.52 ml (31.2 mmol) of pyridine wasadded dropwise to the solution and the resultant mixture was cooled to-5° C. 3.42 ml (27 mmol) of trimethylsilane chloride was added to thesolution and the reaction was conducted at that temperature for 80 min.The reaction liquid was washed with 150 ml of 5% aqueoushydrogencarbonate solution and 150 ml of 10% aqueous common saltsolution and then dried over anhydrous sodium sulfate. The organic layerwas concentrated under reduced pressure to obtain 20.64 g of theintended compound which was positive in sulfuric acid color reaction atRf 0.57 on silica gel TLC with toluene/acetone (1/1) developer.

UV(MeOH)λ max: 235 nm

IR(KBr) ν max: 3520,2973,2884,1748,1713,1373,1236,1171,1100,966,882,

NMR(CDCl₃): (only main peaks)

ε:0.17 (9H, s, Si (CH₃)₃), 0.77 (3H, bs, H-18), 0.91 (3H, t, J=7.3 Hz,H-17), 1.01 (3H, d, J=6.6 Hz, H-21), 1.18 (3H, d, J=6.2 Hz, H-6"), 1.32(3H, d, J=5.9 Hz, H-6'), 1.69 (3H, d, J=0.7 Hz, H-22), 2.01 (3H, s,OCOCH₃ -2'), 2.38 (6H, s, N (CH₃)₂ -3'), 2.59 (1H, t, J=10.3 Hz, H-3 '),3.05 (1H, t, J=9.9 Hz, H-4'), 3.28 (1H, dd, J=9.2&2.6 Hz, H-4"), 3.49(3H, s, OCH₃ -2"), 3.60 (3H, s, OCH₃ -3"), 4.59 (1H, d, J=7.7 Hz, H-1"),4.64 (1H, hr, H-1'), 4.95 (1H, m, H-20), 4.96 (1H, m, H-15), 5.03 (1H,dd, J=10.6&7.7 Hz, H-2'), 5.42 (1H, d, J=10.6 Hz, H-13), 5.62 (1H, d,J=15.8 Hz, H-10), 6.36 (1H, d, J=15.8 Hz, H-11)

FAB-MS: 974 (M+H)⁺

Example 6 Production of 2',4"-di-O-acetyl desmycosin9,20-bis(ethyleneacetal)

200 mg (0.222 mmol) of 2'-O-acetyl desmycosin 9.20-bis(ethyleneacetal)was dissolved in 2 ml of methylene chloride. 35.7 μl (0.444 mmol) ofpyridine was added to the solution. 23.6 μl (0.333 mmol) of acetylchloride was added to the resultant mixture under cooling with ice, andthe reaction was conducted at that temperature for 1 h. 20 ml ofmethylene chloride was added to the reaction liquid and the resultantmixture was washed with 20 ml of 5% aqueous sodium hydro9encarbonatesolution and 20 ml of saturated aqueous common salt solution, and thendried over anhydrous sodium sulfate. The organic layer was concentratedunder reduced pressure, and 244 mg of the residue thus obtained wassubjected to silica gel chromatography (10 g) and eluted withtoluene/acetone (5/1). A fraction which was positive in sulfuric acidcolor reaction at Rf 0.45 on silica gel TLC with toluene/acetone (2/1)developer was taken to obtain 133 mg of the intended compound in theform of a colorless amorphous solid (yield: 64%).

UV(MeOH) λ max: 235 nm

IR(KBr) ν max: 3524,1745,1236,1088,1049cm⁻¹

NMR(CDCl₃): (only main peaks)

ε: 0.77(3H,bs,H-18), 0.92(3H,t,J=7.3 Hz,H-17) 1.00 (3H, d, J=6.6 Hz,H-21), 1.17 (3H, d, J=6.6 Hz, H-6"), 1.32 (3H, d, J=5.9 Hz, H-6'), 1.70(3H, s, H-22), 2.01 (3H, s, OCOCH₃), 2.11 (3H, s, OCOCH₃), 2.39 (6H, s,N (CH₃)₂ -3'), 2.59 (1H, t, J=10.3 Hz, H-3'), 2.89 (1H, m, H-14), 3.31(1H, m, H-5'), 3.48 (3H, s, OCH₃ -2"), 3.52 (3H, s, OCH₃ -3"), 4.44 (1H,dd, J=2.9&9.5 Hz, H-4"), 4.61 (1H, d, J=8.1 Hz, H-1'),5.03(1H,dd,J=10.3&7.3 Hz, H-2'), 5.40 (1H, d, J=10.3 Hz, H-13), 5.63(1H, d, J=15.4 Hz, H-10), 6.36 (1H, d, J=15.4 Hz, H-11)

FAB-MS:944 (M+H)⁺

Example 7 2'-O-acetyl-3,4'-di-O-methanesulfonyl-4 "-O-trimethylsilyldesmycosin 9,20-bis (ethyleneacetal)

10.07 g (10.3 mmol) of 2'-O-acetyl-4"-O-trimethylsilyl desmycosin9,20-bis(ethyleneacetal) was dissolved in 50 ml of toluene. Then 7.20 ml(51.7 mmol) of triethylamine was added to the solution and the resultantsolution was cooled to -15 ° C. 2.8 ml (36.2 mmol) of methanesulfonylchloride was added to the solution, and the reaction was conducted at-10° C for 1 h. 40 ml of toluene was added to the reaction liquid. Theorganic layer was washed with 80 ml of water, 40 ml of 5% aqueous sodiumhydrogencarbonate solution and 40 ml of 10% aqueous common salt solutionand then dried over anhydrous sodium sulfate. The organic layer wasdried to solid under reduced pressure to obtain 12.94 g of the intendedcompound which was positive in sulfuric acid color reaction at Rf 0.55on silica gel TLC with toluene/acetone (3/1) developer. This compoundwas immediately subjected to the subsequent reaction, since it wasunstable. subsequent reaction, since it was unstable.

NMR(CDCl₃): (only main peaks)

ε:0.16 (9H, s, Si(CH₃)₃), 0.88 (3H, d, J=7.3 Hz, H-18), 0.92 (3H, t,J=7.3 Hz, H-17), 1.02 (3H, d, J=6.6 Hz, H-21), 1.18 (3H, d, J=6.2 Hz,H-6"), 1.35 (3H, d, J=5.9 Hz, H-6'), 1.69 (3H, d, J=0.7 Hz, H-22), 2.04(3H, s, OCOCH₃ -2'), 2.39 (6H, s, N (CH₃)₂ -3'), 2.93 (1H, t, J=10.3 Hz,H-3'), 3.10 (3H, s, OSO₂ CH₃), 3.14 (3H, s, OSO₂ CH₃), 3.28 (1H, dd,J=9.5&2.6 Hz H-4"), 3.47 (3H, s, OCH₃ -2"), 3.59 (3H, s, OCH₃ -3"), 4.22(1H, t, J=9.9 Hz, H-4'), 4.57(1H, d, J=7.7 Hz, H-1"), 4.60 (1H, br,H-1'), 4.75 (1H, br, H-3), 4.93(1H, m, H-15), 4.96 (1H, m, H-20), 5.03(1H, dd, J=10.3&8.0 Hz, H-2'), 5.47 (1H, d, J=11.0 Hz, H-13), 5.54 (1H,d, J=15.8 Hz, H-10), 6.34 (1H, d, J=15.8 Hz, H-11)

FAB-MS: 1130 (M+H)⁺

Example 8 2',4"-Di-O-acetyl-3,4'-di-O-methanesulfonyl desmycosin9,20-bis(ethyleneacetal)

109 mg (0.115 mmol) of 2',4"-di-O-acetyldesmycosin9,20-bis(ethyleneacetal) was dissolved in 0.5 ml of toluene.80.2 ml(0.575 mmol) of triethylamine was added to the solution, and theresultant mixture was cooled with ice. 31.2 ml (0.403 mmol) ofmethanesulfonyl chloride was added to the mixture, and the reaction wasconducted at that temperature for 1.5 h. 10 ml of ethyl acetate wasadded to the reaction liquid, and the resultant mixture was washed with10 ml of 5% aqueous sodium hydrogencarbonate solution and 10 ml ofsaturated aqueous common salt solution, and then dried over anhydroussodium sulfate. The organic layer was concentrated to dryness underreduced pressure to obtain 134 mg of the intended compound which waspositive in sulfuric acid color reaction at Rf 0.64 on silica gel TLCwith toluene/acetone (2/1) developer. This compound was immediatelysubjected to the subsequent reaction, since it was unstable.

NMR(CDCl₃): (only main peaks)

ε:0.88 (3H, d, J=7.3 Hz, H-18), 0.93 (3H, t, J=7.3 Hz, H-17), 1.03 (3H,d, J=6.8Hz, H-21), 1.17 (3H, d, J=6.2 Hz, H-6"), 1.36 (3H, d, J=5.9 Hz,H-6'), 1.70 (3H, s, H-22), 2.04 (3H, s, OCOCH₃), 2.11 (3H, s, OCOCH₃),2.40 (6H, s, N (CH₃)₂ -3'), 2.84 (1H, m, H-14), 2.94 (1H, t, J=10.3 Hz,H-3'), 3.04 (1H, dd, J=2.9&8.1 Hz, H-2"), 3.10 (3H, s, OSO₂ CH₃), 3.12(3H, s, OSO₂ CH₃), 3.46 (3H, s, OCH₃ -2"), 3.52 (3H, s, OCH₃ -3"), 4.22(1H, t, J=9.9 Hz, H-4'), 4.45 (1H, rid, J=2.6&9.9 Hz, H-4'), 4.60 (1H,d, J=8.1 Hz, H-1"), 5.03 (1H, dd, J=10.3&7.7 Hz, H-2'), 5.46 (1H, d,J=10.6 Hz, H-13), 5.55 (1H, d, J=15.6 Hz, H-10), 6.35 (1H, d, J=15.6 Hz,H-11)

FAB-MS: 1100(M+H)⁺

Example 9 2'-O-acetyl-3,4'-di-O-benzylsulfonyl-4"-O-trimethylsilyldesmycosin 9,20-bis(ethyleneacetal)

1.0 g (1.03 mmol) of 2'-O-acetyl-4"-O-trimethylsilyl desmycosin9,20-bis(ethyleneacetal) was dissolved in 10 ml of toluene.0.46 ml (3.4mmol) of triethylamine was added to the solution, and the resultantmixture was cooled to -15° C. 430 mg (2.3 mmol) of benzylsulfonylchloride was added to the solution, and the reaction was conducted at-10° C. for 1.5 h. 40 ml of toluene was added to the reaction liquid.The organic layer was washed with 50 ml of water, 50 ml of 5% aqueoussodium hydrogencarbonate solution and 50 ml of 10% aqueous common saltsolution and then dried over anhydrous sodium sulfate. The organic layerwas concentrated to dryness under reduced pressure to obtain 1.34 g ofthe intended compound which was positive in sulfuric acid color reactionat Rf 0.57 on silica gel TLC with toluene/acetone (4/1) developer. Thiscompound was immediately subjected to the subsequent reaction, since itwas unstable.

NMR(CDC₃): (only main peaks)

ε:0.16 (9H, s, Si(CH₃)₃), 0.81 (3H, d, J=7.3 Hz, H-18), 0.94 (3H, t,J=7.3 Hz, H-17), 1.01 (3H, d, J=6.6 Hz, H-21), 1.18 (3H, d, J=6.2 Hz,H-6"), 1.31 (3H, d, J=6.2 Hz, H-6'), 1.69 (3H, d, J=0.7 Hz, H-22), 1.99(3H, s, OCD CH₃ -2'), 2.47 (6H, s, N (CH₃)₂ -3"), 2.94 (1H, t, J=10.3Hz, H-3'), 3.29 (1H, dd, J=9.2&2.6 Hz, H-4'), 3.47 (3H, s, OCH₃ -₂ "),3.59 (3H, s, OCH₃ -3"), 4.33 (1H, t, J=9.9 Hz, H-4'), 4.40 (1H, bd,J=15.0 Hz, OSO₂ C HHph), 4.51 (1H, m, H-1'), 4.53 (2H, m, OSO₂ CH₂ ph),4.57 (1H, m, SO₂ CHHph), 4.58 (1H, d, J-8.1 Hz, H-1"), 4.87 (1H, br,H-3), 4.97 (1H, m, H-15), 5.03 (1H, dd, J=10.3&7.7 Hz, H-2'), 5.50 (1H,d, J=10.6 Hz, H-13), 5.55 (1H, d, J=15.8 Hz, H-10), 6.36 (1H, d, J=15.8Hz, H-11), 7.36-7.42 (lOH, m, 2 x ph)

FAB-MS: 1282 (M+H)⁺

Example 102'-O-Acetyl-4'-deoxy-4'-iodo-3-O-methanesulfonyl-4"-O-trimethylsilyldesmycosin 9,20-bis(ethyleneacetal)

12.94 g (11.5 mmol) of2'-O-acetyl-3,4'-di-O-methanesulfonyl-4"-O-trimethylsilyl desmycosin9,20-bis(ethyleneacetal) was dissolved in 60 ml of methyl ethylketone.2.58 g (17.2 mmol) of sodium iodide was added to the solution,and the reaction was conducted in a dark place at 85° C. for 1 h. Thereaction liquid was cooled to room temperature to form precipitates,which were filtered and washed with 5 ml of toluene. The wash solutionwas combined with the mother liquor, and the resultant mixture wasconcentrated under reduced pressure. 60 ml of toluene and 60 ml of waterwere added to the concentrate to divide it into layers. Then the organiclayer was washed with 40 ml of 10% sodium thiosulfate and 40 ml ofwater, dried over anhydrous sodium sulfate and concentrated to drynessunder reduced pressure to obtain 10.73 g of the intended compound whichwas positive in sulfuric acid color reaction at Rf 0.51 on silica gelTLC with toluene/acetone (4/1) developer.

UV(MeOH) λ max: 235 nm

IR(KBr) ν max: 3443,2937,2940,2886,1746,1360,1233,1173,1101,1049,966,909,882,843 cm⁻¹

NMR(CDCl₃): (only main peaks)

ε:0.16 (9H, s, Si (CH₃)₃), 0.89 (3It, d, J=7.3 Hz, H-18), 0.92 (3H, t,J=7.3 Hz, H-17), 1.02 (3H, d, J=7.0 Hz, H-21), 1.18 (3H, d, J=6.2 Hz,H-6"), 1.51 (3H, d, J=5.9 Hz, H-6'), 1.69 (3H, d, J=0.7 Hz, H-22), 2.02(3H, s, OCOCH₃ -2'), 2.42 (6H, s, N (CH₃)₂ -3'), 3.12 (3H, s, OSO₂ CH₃-3), 3.47 (3H, s, OCH₃ -2"), 3.59 (3H, s, OCH₃ -3"), 4.57 (1H, d, J=8.1Hz, H-1"), 4.57 (1H, br, H-1'), 4.77 (1H, br, H-3), 4.91 (1H, dd,J=9.9&7.3 Hz, H-2') 4.93 (1H, m, H-15), 4.98 (1H, br, H-20), 5.47 (1H,d, J=10.6 Hz, H-13), 5.54 (1H, d, J=15.8 Hz, H-10), 6.34 (1H, d, J=15.8Hz, H-11)

FAS-MS: 1162 (M+H)⁺

Example 11 2',4"-Di-O-acetyl-4'-deoxy-4'-iodo-3-O-methanesulfonyldesmycosin 9,20-bis(ethyleneacetal)

134 mg (0.115 mmol) of 2',4"-di-O-acetyl-3,4'-di-O-methanesulfonyldesmycosin 9,20-bis(ethyleneacetal) was dissolved in 1 ml of methylethyl ketone. 25.7 mg (0.173 mmol) of sodium iodide was added to thesolution and the resultant mixture was heated under reflux for 30 min.ml of ethyl acetate was added to the reaction liquid. The obtainedmixture was washed with 10 ml of 5% aqueous sodium hydrogencarbonatesolution and 10 ml of saturated aqueous common salt solution, and thendried over anhydrous sodium sulfate. The organic layer was concentratedunder reduced pressure and 128 mg of the obtained residue was purifiedby a dispensing silica gel TLC with toluene/acetone (3/1) developer. 86mg (yield: 72%) of the intended compound which was positive in sulfuricacid color reaction at Rf 0.61 on TLC with the same developer wasobtained from 2',4"-di-O-acetyl desmycosin 9,20-bis(ethyleneacetal) bytwo steps.

UV(MeOH) λ max: 234 nm

IR(KBr) ν max: 2975,2938,2884,1740,1377,1233,1171,1088,1049,963,909 cm⁻¹

NMR(CDCl₃): (only main peaks)

ε:0.89(3H, d,J=7.3 Hz, H-18), 0.92 (3H, t, J=7.3 Hz, H-17), 1.02 (3H, d,J=6.6 Hz, H-21), 1.17 (3H, d, J=5.9 Hz, H-6"), 1.51 (3H, d, J=5.9 Hz,H-6'), 1.70 (3H, s, H-22), 2.02 (3H, s, OCOCH₃), 2.11 (3H, s, OCOCH₃),2.42 (6H, s, N(CH₃)₂ -3'), 3.04 (1H, dd, J=2.9&8.11 Hz, H-2"), 3.12 (3H,s, OSO₂ CH₃ -3), 3.46 (3H, s, OCH₃ -2"), 3.52 (3H, s, OCH3-3"), 4.47(1H, rid, J=2.9&11.7 Hz, H-4"), 4.60 (1H, d, J=8.1 Hz, H-1"), 5.46 (1H,d, J=11.0 Hz, H-13), 5.55 (1H, d, J=15.4 Hz, H-10), 6.35 (1H, d, J=15.4Hz, H-11)

FAB-MS: 1134(M+H)⁺

Example 122'-O-Acetyl-3-O-benzylsulfonyl-4'-deoxy-4'-iodo-4"-O-trimethylsilyldesmycosin 9,20-bis(ethyleneacetal):

1.23 g (0.96 mmol) of2'-O-acetyl-3,4'-di-O-benzylsulfonyl-4"-Otrimethylsilyl desmycosin9,20-bis(ethyleneacetal) was dissolved in 10 ml of methyl ethyl ketone.216 mg (1.4 mmol) of sodium iodide was added to the solution, and thereaction was conducted in a dark place at 85° C. for 30 min. Thereaction liquid was cooled to room temperature to form precipitates,which were filtered and washed with 5 ml of toluene. The wash solutionwas combined with the mother liquor, and the resultant mixture wasconcentrated under reduced pressure. 30 ml of toluene and 30 ml of waterwere added to the concentrate to divide it into layers. Then, theorganic layer was washed with 30 ml of saturated aqueous sodiumhydrogencarbonate solution and 30 ml of 10% aqueous common saltsolution, dried over anhydrous sodium sulfate and concentrated todryness under reduced pressure to obtain 1.22 g of the intended compoundwhich was positive in sulfuric acid color reaction at Rf 0.51 on silicagel TLC with toluene/acetone (4/1) developer.

UV(MeOH) λ max: 235 nm

IR(KBr) ν max: 3488,2938,2886,1748,1456,1373,1233,1171,1101,1049,968,882 cm⁻¹

NMR(CDCl₃): (only main peaks)

ε:0.17 (9H, s, Si(CH₃)₃), 0.81 (3H, d, J=7.3 Hz, H-18), 0.93 (3H, t,J=7.3 Hz, H-17), 1.01 (3H, d, J=6.6 Hz, H-21), 1.18 (3H, d, J=6.2 Hz,H-6 "), 1.49 (3H, d, J=5.5 Hz, H-6'), 1.68 (3H, s, H-22), 1.97 (3H, s,OCOCH₃ -2'), 2.41 (6H, s, N(CH₃)₂ -3'), 2.78 (1H, t, J=10.3 Hz, H-3'),3.48 (3H, s, OCH₃ -2"), 3.59 (3H, s, OCH₃ -3"), 4.40 (1H, m, H-1), 4.40(1H, m, OSO₂ CHHHph), 4.58 (1H, d, J=8.1 Hz, H-1"), 4.58 (1H, m, OSO₂CHHph), 4.87 (1H, dd, J=9.9&7.7 Hz, H-2'), 4.96 (1H, m, H-15), 5.51 (1H,d, J=11.4 Hz, H-13), 5.54 (1H, d, J=15.8 Hz, H-10), 6.36 (1H, d, J=15.8Hz, H-11), 7.40 (SH, s, ph)

FAB-MS: 1238 (M+H)

Example 13 2'-O-Acetyl-3,4'-dideoxy desmycosin 9,20-bis(ethyleneacetal)

10.70 g (9.2 mmol) of2'-O-acetyl-4'-deoxy-4'-iodo-3-O-methanesulfonyl-4"-O-trimethylsilyldesmycosin 9,20-bis(ethyleneacetal) was dissolved in 50 ml of methanol.3.82 g (27.6 mmol) of potassium carbonate and then a suspension of 6.4 g(wet weight) (5 ml) of a Raney nickel (NDT-65; a product of Kawaken FineChemicals Co., Ltd.) in 8 ml of methanol were added to the solution toconduct the catalytic reduction under a hydrogen pressure of 3 kg/cm²for 2 h. The catalyst was filtered out through Celite, and the motherliquid was concentrated under reduced pressure. 100 ml of ethyl acetateand 100 ml of water were added to the concentrate to divide it intolayers. The organic layer was washed with 100 ml of 20% aqueous commonsalt solution and then concentrated under reduced pressure. 0.86 ml ofacetic anhydride was added to the concentrate to conduct the reaction atroom temperature for 1.5 h. After washing with 30 ml of 5% aqueoussodium hydrogencarbonate solution and 30 ml of 20% aqueous common saltsolution, the organic layer was dried over anhydrous sodium sulfate andthen dried to solid under reduced pressure to obtain 7.46 g of theintended compound which was positive in sulfuric acid color reaction atRf 0.44 on silica gel TLC with chloroform/toluene (10/1) developer.

303 mg of the intended compound was obtained from 480 mg of2'-O-acetyl-3-O-benzylsulfonyl-4'-dioxy-4'-iodo-4"-O-trimethylsilyldesmycosin 9,20-bis(ethyleneacetal) by reduction followed by acetylationin the same manner as that described above.

71 mg of the intended compound was obtained from 100 mg of2',4"-di-O-acetyl-4'-deoxy-4'-iodo-3-O-methanesulfonyl desmycosin9,20-bis(ethyleneacetal) by reduction followed by acetylation in thesame manner as that described above.

UV (MeOH) λ max: 235 nm

IR(KBr) ν max: 3476,2973,2938,2882,1744,1373,1238,1167,1061,961cm ⁻¹

NMR (CDCl₃): (only main peaks)

ε:0.82 (3H, bd, J=5.5 Hz, H-18), 0.92 (3H, t, J=7.3 Hz, H-17), 1.00 (3H,d, J=6.6 Hz, H-21), 1.23 (3H, d, J=6.2 Hz, H-6'), 1.26 (3H, d, J=6.2 Hz,H-6"), 1.35 (1H, m, H-4' a), 1.71 (1H, m, H-4" b), 1.73 (3H, d, J=1.1Hz, H-22), 2.04 (3H, s, OCOCH₃ -2'), 2.26 (GH, s, N (CH₃)₂ -3'), 2.68(1H, ddd, J=12.3&10.4&4.4 Hz, H-3'), 3.18 (1H, br, H-4"), 3.48 (3H, s,OCH₃ -2"), 3.61 (3H, s, OCH₃ -3"), 4.31 (1H, d, J=7.7 Hz, H-1'), 4.55(1H, d, J=7.7 Hz, H-1"), 4.80 (1H, dd, J=10.4&?7.7 Hz, H-2'), 4.90 (1H,m, H-15), 4.95 (1H, bt, J=5.1 Hz, H-20), 5.42 (1H, d, J=10.6 Hz, H-13),5.62 (1H, d, J=15.8 Hz, H-10), 6.36 (1H, d, J=15.8 Hz, H-11)

FAB-MS : 870 (M+H)⁺

Example 14 2'-O-Acetyl-3,4'-dideoxy-4"-oxo desmycosin9,20-bis(ethyleneacetal)

491 mg (3.68 mmol) of N-chlorosuccinimide was suspended in 8 ml oftoluene, and the resultant suspension was cooled to 0° C. 0.4 ml (5.5mmol) of dimethyl sulfide was added to the suspension and the resultantmixture was stirred at that temperature for 20 min. The resultantsolution was cooled to -20° C., then 4 ml of a solution of 800 mg (0.92mmol) of 2'-O-acetyl-3,4'-dideoxy desmycosin 9,20-bis(ethyleneacetal) intoluene was added to the resultant solution, and the reaction wasconducted at that.temperature for 1.5 h. 0.64 ml (4.6 mmol) oftriethylamine was added to the reaction liquid and the reaction wasconducted for additional 20 min. The reaction liquid was washed with 15ml of 10% aqueous common salt solution twice, dried over anhydroussodium sulfate and dried to solid under reduced pressure to obtain 755mg of the intended compound which was positive in sulfuric acid colorreaction at Rf 0.65 on silica gel TLC with chloroform/methanol (5/1)developer.

UV(MeOH) λ max: 235 nm

IR(KBr) ν max: 3441,2971,2938,2882,1744,1373,1240,1169,1117,1057, 974cm⁻¹

NMR(CDCl₃): (only main peaks)

ε:0.83 (3H, d, J=5.9 Hz, H-18), 0.94 (3H, t, J=7.3 Hz, H-17), 1.00 (3H,d, J=6.6 Hz, H-21), 1.24 (3H, d, J=5.9 Hz, H-6'), 1.35 (3H, d, J=7.0 Hz,H-6"), 1.38 (lit, m, H-4' a) , 1.73 (1H, m, H-4' b) 1.76 (3H, d, J=1.1Hz, H-22), 2.04 (3H, s, OCOCH₃ -2'), 2.26 (6H, s, N (CH₃)₂ -3'), 3.46(3H, s, OCH₃ -2"), 3.50 (3H, s, OCH₃ -3"), 3.74 (1H, t, J=3.3 Hz, H-2"),4.17 (1H, q, J=7.0 Hz, H-5"), 4.26 (1H, d, J=3.7 Hz, H-3"), 4.32 (1H, d,J=7.7 Hz, H-1'), 4.81 (1H, dd, J=10.6&7.7 Hz, H-2'), 4.83 (1H, d, J=2.9Hz, H-1"), 4.92 (1H, m, H-15), 4.95 (1H, bt, J=5.1 Hz, H-20), 5.39 (1H,d, J=10.3 Hz, H-13), 5.67 (1H, d, J=15.8 Hz, H-10), 6.37 (1H, d, J=15.8Hz, H-11)

FAB-MS:868(M+H) ⁺

Example 15 3,4'-Dideoxymycaminosyltylonolide 9,20-bis (ethyleneacetal)

100 mg (0.115 mmol) of 2'-O-acetyl-3,4'-dideoxy-4"-oxo desmycosin9,20-bis(ethyleneacetal) was dissolved in 1 ml of methanol. 0.115 ml of1N-NaOH solution was added to the solution at 0 ° C., and the reactionwas conducted at that temperature for 1 h.Then 40 μl of concentratedammonia water was added to the reaction mixture and the temperature waselevated to conduct the reaction at 60° C. for 2 h. 5 ml of chloroformwas added to the reaction liquid, and the organic layer was washed with5 ml of 10% aqueous common salt solution four times. The organic layerwas dried to solid under reduced pressure to obtain 74 mg of theintended compound which was positive in sulfuric acid color reaction atRf 0.31 on silica gel TLC with chloroform/methanol (5/1 ) developer.

UV (MeOH) A max: 235 nm

IR(KBr) λ max: 3449,2938,2880,1730,1642,1458,1381,1169,1111,1049, 974cm⁻¹

NMR(CDCl₃): (only main peaks)

ε:0.93 (3H, t, J=7.3 Hz, H-17), 0.99 (3H, d, J=6.6 Hz, H-18), 1.02 (3H,d, J=7.0 Hz, H-21), 1.24 (3H, d, J=5.9 Hz, H-6'), 1.78 (3H, d, J=1.1 Hz,H-22), 2.35 (6H, s, N (CH₃)₂ -3'), 3.30 (1H, dd, J=10.3&7.3 Hz, H-2'),4.29 (1H, d, J=7.0 Hz, H-1'), 4.84 (1H, m, H-15), 5.01 (1H, bt, J=5.1Hz, H-20), 5.34 (1H, d, J=9.9 Hz, H-13), 5.66 (1H, d, J=15.8 Hz, H-10),6.42 (1H, d, J=15.8 Hz, H-11)

FAB-MS:654 (M+H)⁺ , 676 (M+Na)⁺

Example 16 3,4'-Dideoxymycaminosyltylonolide

26 mg (0.05 mmol) of 3,4'-dideoxymycaminosyltylonolide9,20-bis(ethyleneacetal) was dissolved in 0.2 ml of tetrahydrofuran. 0.2ml of 1 N hydrochloric acid was added to the solution, and the reactionwas conducted at room temperature for 1.5 h. The reaction liquid wasdiluted with water and then 3 ml of chloroform was added thereto. Theorganic layer was washed with 2 ml of 5% aqueous sodiumhydrogencarbonate solution and 2 ml of 10% aqueous common salt solutionand then dried over anhydrous sodium sulfate. The organic layer wasdried to solid under reduced pressure to obtain 20 mg of the intendedcompound which was positive in sulfuric acid color reaction at Rf 0.25on silica gel TLC with chloroform/methanol (5/1) developer.

UV(MeOH) λ max: 283 nm

IR (KBr) ν max: 3436,2967,2878,1725,1676,1591,1458,1383,1316,1167,1071,984 cm⁻¹

NMR (CDCl₃): (only main peaks) ε:0.94 (3H, t, J=7.3 Hz, H-17), 1.04 (3H,d, J=6.6 Hz, H-18), 1.20 (3H, d, J=6.2 Hz, H-6'), 1.21 (3H, d, J=6.6 Hz,H-21), 1.85 (3H, d, J=1.1 Hz, H-22), 2.29 (6H, s, N (CH₃)₂ -3'), 2.90(1H, m, H-14), 3.20 (1H, dd, J=7.3&10.3 Hz, H-2'), 4.19 (1H, d, J=7.3Hz, H-1'), 4.88 (1H, m, H-15), 5.84 (1H, d, J=10.6 Hz, H-13), 6.35 (1H,d, J=15.6 Hz, H-10), 7.30 (1H, d, J=15.6 Hz, H-11), 9.69 (1H, s, H-20)

FAB-MS:566(M+H)⁺

Example 17 3,2', 4"-Tri-O-acetyl desmycosin 9,20-bis(ethyleneacetal)

1.00 g (0.922 mmol) of 3,2',4",4"'-tetra-O-acetyltylosin was dissolvedin 5 ml of toluene.0.61 ml (3.69 mmol) of ethyl orthoformate, 0.51 ml(9.22 mmol) of ethylene glycol and 321 mg (1.38 mmol) ofdl-camphorsulfonic acid were successively added to the solution. Afterconducting the reaction at 50 ° C. for 2 h, 10 ml o f toluene was addedto the reaction liquid. The resultant mixture was washed with 15 ml of5% aqeous sodium hydrogencarbonate solution and 15 ml of saturatedaqueous common salt solution and then dried over anhydrous sodiumsulfate. The organic layer was concentrated under reduced pressure andthe resultant concentrate was subjected to the silica gel chromatography(55 g) and eluted with toluene/acetone (5/1). A fraction which waspositive in sulfuric acid color reaction at Rf 0.38 on silica gel TLCwith toluene/acetone (2/1) developer was taken to obtain 525 mg (yield:58%) of the intended compound in the form of a colorless amorphoussolid.

UV (MeOH) λ max: 235 nm

IR(KBr) ν max: 3468,2976,2938,2882,1742,1372,1236,1175,1086,1049 cm⁻¹

NMR(CDCl₃): (only main peaks)

ε: 0.84 (3H, hr, H-18), 0.90 (3H, t, J=7.3 Hz, H-17), 0.99 (3H, d, J=5.9Hz, H-21), 1.16 (3H, d, J=6.6 Hz, H-6"), 1.31 (3H, d, J=5.9 Hz, H-6'),1.71 (3H, s, H-22), 2.05 (3H, s, OCOCH₃), 2.11 (GH, s, 2×OCOCH₃), 2.39(6H, s, N (CH₃)₂ -3'), 2.91 (1H, m, H-14), 3.28 (1H, m, H-5'), 3.45 (3H,s, OCH₃ -2"), 3.52 (3H, s, OCH₃ -3"), 4.29 (1H, d, J=6.6 Hz, H-1'), 4.43(1H, dd, J=2.2&10.3 Hz, H-4"), 4.60 (1H, d, J=8.1 Hz, H-1"), 4.81 (1H,m, H-15), 4.90 (1H, bs, H-20), 5.42 (1H, d, J=10.3 Hz, H-13), 5.61 (1H,d, J=16.1 Hz, H-10), 6.49 (1H, d, J=16.1 Hz, H-11)

FAB-MS: 986 (M+H)⁺

Example 18 2',4"-Di-O-acetyl-2,3-dehydro-3-deoxy desmycosin9,20-bis(ethyleneacetal)

100 mg (0 101 mmol) of 3,2',4"-tri-O-acetyl desmycosin9,20-bis(ethyleneacetal) was dissolved in 1 ml of tetrahydrofuran. 9.7mg (0.404 mmol) of sodium hydride was added to the solution undercooling with ice, and the reaction was conducted at room temperature for1.5 h. 20 ml of ethyl acetate was added to the reaction liquid, and theresultant mixture was washed with water and dried over anhydrous sodiumsulfate. The organic layer was concentrated under reduced pressure, and110 mg of the concentrate thus obtained was purified by a dispensingsilica gel TLC with toluene/acetone (2/1) developer to obtain 80 mg(yield: 85%) of the intended compound which was positive in sulfuricacid color reaction at Rf 0.49 on silica gel TLC with the same developeras above.

UV(MeOH) λ max: 218 nm

IR(KBr) ν max: 3468,2975,2938,2882,1746,1373,1235,1171,1086,1051 cm⁻¹

NMR(CDCl₃): (only main peaks)

ε: 0.95 (3H, t, J=7.3 Hz, H-17), 1.17 (3H, d, J=6.6 Hz, H-6"), 1.33 (3H,d, J=6.6 Hz, H-6"), 1.70 (3H, s, H-22), 2.05 (3H, s, OCOCH₃), 2.11 (3H,s, OCOCH₃), 2.40 (GH, s, N (CH₃)₂ -3'), 2.57 (1H, t, J=10.3 Hz, H-3'),2.91 (1H, m, H-14), 3.33 (1H, m, H-5'), 3.48 (3H, s, OCH₃ -2"), 3.52(3H, s, OCH₃ -3"), 4.62 (1H, d, J=8.1 Hz, H-1"), 4.87 (1H, m, H-15),4.97 (1H, bs, H-20), 5.05 (1H, dd, J=7.3 & 10.3 Hz, H-2'), 5.33 (1H, d,J=10.3 Hz, H-13), 5.48 (1H, d, J=15.4 Hz, H-10), 5.54 (1H, d, J=15.4 Hz,H-2), 6.24 (1H, d, J=15.4 Hz, H-11), 6.70 (1H, dd, J=15.4 & 9.5 Hz, H-3)

FAB-MS: 926 (M+H)⁺

Example 19 2',4"-Di-O-acetyl-2,3-dehydro-3-deoxy-4'-O-methanesulfonyldesmycosin 9,20-bis(ethyleneacetal)

50 mg (0.0539 mmol) of 2',4"-di-O-acetyl-2,3-dehydro-3-deoxy desmycosin9,20-bis(ethyleneacetal) was dissolved in 0.5 ml of methyl ethylketone.22.5 μl (0.161 mmol) of triethylamine was added to the solutionand then a solution of 6.3 μl (0.0808 mmol) of methanesulfonyl chloridein 100 μl of methyl ethyl ketone was added to the solution under coolingwith ice to conduct the reaction at that temperature for 15 min. 10 mlof ethyl acetate was added to the reaction liquid and the resultantmixture was washed with 10 ml of 5% aqueous sodium hydrogencerbonatesolution and 10 ml of saturated aqueous common salt solution, and thendried over anhydrous sodium sulfate. The organic layer was concentratedto solid under reduced pressure to obtain 55 mg of the intended compoundwhich was positive in sulfuric acid color reaction at Rf 0.51 on silicagel TLC with toluene/acetone (4/1) developer.

NMR (CDCl₃): (only main peaks)

ε: 0.95 (3H, t, J=7.3 Hz, H-17), 1.17 (3H, d, J=6.6 Hz, H-6"), 1.38 (3H,d, J=5.9 Hz, H-6'), 1.70 (3H, s, H-22), 2.06 (3H, s, OCOCH₃), 2.11 (3H,s, OCOCH₃), 2.40 (6H, s, N (CH₃)₂ -3'), 3.05 (1H, dd, J=8.1 & 2.9 Hz,H-2"), 3.11 (3H, s, OSO₂ CH₃ -4'), 3.48 (3H, s, OCH₃ -2"), 3.52 (3H, s,OCH₃ -3"), 4.24 (1H, t, J =9.5 Hz, H-4'), 4.82 (1H, d, J=8.1 Hz, H-1"),5.08 (1H, dd, J=7.3 & 10.3 Hz, H-2'), 5.33 (1H, d, J=10.3 Hz, H-13),5.48 (1H, d, J=15.4 Hz, H-10), 5.55 (1H, d, J=15.4 Hz, H-2), 6.24 (1H,d, J=15.4 Hz, H-11), 6.68 (1H, dd, J=15.4 & 9.5 Hz, H-3)

FAB-MS: 1004 (M+H)⁺

Example 20 2',4"-Di-O-aeetyl-2,3-dehydro-3,4"-dideoxy-4'-iodo desmyeosin9,20-bis(ethyleneacetal)

1.88 g (2.03 mmol) of 2',4"-Di-O-aeetyl-2,3-dehydro-3-deoxy desmycosin9,20-bis(ethyleneacetal) was dissolved in 20 ml of methyl ethyl ketone.0.85 ml (6.09 mmol) of triethylamine was added to the solution and thena solution of 0.20 ml (2.64 mmol) of methanesulfonyl chloride in 1.5 mlof methyl ethyl ketone was added to the resultant mixture under coolingwith ice. After conducting the reaction at that temperature for 30 min,907 mg (6.09 mmol) of sodium iodide was added to the reaction liquid,and the resultant mixture was heated under reflux for 30 min. Thereaction liquid was concentrated under reduced pressure, and then 50 mlof ethyl acetate was added to the concentrate. After washing with 50 mlof 5% aqueous sodium hydrogencarbonate solution and 50 ml of saturatedaqueous common salt solution followed by drying over anhydrous sodiumsulfate, the organic layer was concentrated under reduced pressure anddried in vacuo to obtain 2.10 g of a colorless amorphous solid mainlycomprising the intended compound.

UV(MeOH) λ max: 216 nm

IR(KBr) ν max: 2975,2936,2880,1750,1717,1373,1233,1171,1090,1049 cm⁻¹

NMR(CDCl₃): (only main peaks)

ε:0.95 (3H, t, J=7.3 Hz, H-17), 1.17 (3H, d, J=6.6 Hz, H-6"), 1.53 (3H,d, J=5.1 Hz, H-6'), 1.69 (3H, s, H-22), 2.04(3H, s, OCOCH₃), 2.11 (3H,s, OCOCH₃), 3.05 (1H, dd, J=2.9 & 8.1 Hz, H-2"), 3.48 (3H, s, OCH₃ -2"),3.52 (3H, s, OCH₃ -3"), 4.62 (1H, d, J=8.1 Hz, H-1"), 5.33 (1H, d,J=10.3 Hz, H-13), 5.47 (1H, d, J=15.4 Hz, H-10), 5.55 (1H, d, J=15.4 Hz,H-2), 6.24 (1H, d, J=15.4 Hz, H-11), 6.69 (1H, dd, J=15.4 & 9.5 Hz, H-3)

FAB-MS: 1036 (M+H)⁺

Example 21 3,2',4"-Tri-O-acetyl-4'-O-methanesulfonyl desmycosin9,20-bis(ethyleneacetal)

100 mg (0.101 mmol) of 3,2',4"-tri-O-acetyl-desmycosin 9,20-bis(ethyleneacetal) was dissolved in 1 ml of methyl ethyl ketone.63.1 μl (0.455 mmol) of triethylamine was added to the solution and thena solution of 30.5 μl (0.394 mmol) of methanesulfonyl chloride in 100 μlof methyl ethyl ketone was added to the resultant mixture under coolingwith ice. After conducting the reaction at that temperature for 30 min,10 ml of chloroform was added to the reaction liquid. After washing with10 ml of 5% aqueous sodium hydrogencarbonate solution and 10 ml ofsaturated aqueous common salt solution followed by drying over anhydroussodium sulfate, the organic layer was concentrated under reducedpressure and dried in vacuo to obtain 115 mg of a colorless amorphoussolid mainly comprising the intended compound.

NMR(CDCl₃): (only main peaks)

ε: 0.84 (3H, br, H-18), 0.90 (3H, t, J=7.3 Hz, H-17), 0.99 (3H, d, J=5.9Hz, H-21), 1.17 (3H, d, J=6.6 Hz, H-6"), 1.36 (3H, d, J=5.9 Hz, H-6'),1.70 (3H, s, H-22), 2.06 (3H, s, OCOCH₃), 2.10 (3H, s, OCOCH₃), 2.11(3H, s, OCOCH₃), 2.39 (6H, s, N (CH₃)₂ -3'), 3.03 (1H, dd, J=2.9 & 8.1Hz, H-2"), 3.10 (3H, s, OSO₂ -CH₃ -4'), 3.45 (3H, s, OCH₃ -2"), 3.51(3H, s, OCH₃ -3"), 4.22 (1H, t, J=9.5 Hz, H-4'), 4.43 (1H, dd, J=2.2 &g.5 Hz, H-4"), 4.60 (1H, d, J=8.1 Hz, H-1"), 4.81 (1H, m, H-15), 4.88(1H, t, J=5.1 Hz, H-20), 5.42 (1H, d, J=10.3 Hz, H-13), 5.61 (1H, d,J=16.1 Hz, H-10), 6.48 (1H, d, J=16.1 Hz, H-11),

FAB-MS: 1064 (M+H)⁺

Example 22 3,2',4"-Tri-O-acetyl-4'-deoxy-4'-iodo desmycosin9,20bis(ethyleneacetal)

100 mg (0.101 mmol) of 3,2',4"-tri-O-acetyl-desmycosin9,20bis(ethyleneacetal) was dissolved in 1 ml of methyl ethyl ketone.70.7 μl (0.507 mmol) of triethylamine was added to the solution and thena solution of 11.8 μl (0.152 mmol) of methanesulfonyl chloride in 0.1 mlof methyl ethyl ketone was added to the resultant mixture under coolingwith ice. After stirring the resultant mixture at that temperature for30 min to complete the mesylation reaction, 45.4 mg (0.303 mmol) ofsodium iodide was added to the reaction liquid, and the resultantmixture was heated under reflux for 30 min. The reaction liquid wasconcentrated under reduced pressure, 20 ml of ethyl acetate was addedthereto. After washing with 20 ml of 5% aqueous sodium hydrogencarbonatesolution and 20 ml of water followed by drying over anhydrous sodiumsulfate, the organic layer was concentrated under reduced pressure anddried in vacuo to obtain a concentrate. It was purified by a dispensingsilica gel TLC with toluene/acetone (3/1) developer to obtain 98.5 mg(yield: 89%) of the intended compound which was positive in sulfuricacid color reaction at Rf 0.66 on TLC with the same developer.

UV(MeOH) λ max: 235 nm

IR(KBr) ν max: 2976,2938,2884,1744,1373,1235,1049 cm⁻¹

NMR(CDCl₃): (only main peaks)

ε: 0.85 (3H, br, H-18), 0.90 (3H, t, J=7.3 Hz, H-17), 0.99 (3H, d, J=6.2Hz, H-21), 1.17 (314, d, J=6.2 Hz, H-6"), 1.51 (3H, d, J=5.5 Hz, H-6'),1.71 (3H, d, J=1.1 Hz, H-22), 2.05(3H, s, OCOCH₃), 2.11 (6H, s,2×OCOCH₃), 2.42 (6H, s, N(CH₃)₂ -3'), 2.91 (1H, m, H-14), 3.03 (1H, rid,J=2.9 & 8.1 Hz, H-2"), 3.45 (3H, s, OCH₃ -2"), 3.52 (3H, s, OCH₃ -3"),4.27 (1H, br, H-1'), 4.43 (1H, dd, J=2.6 & 9.9 Hz, H-4"), 4.60 (1H, d,J=8.1 Hz, H-1"), 4.82 (1H, m, H-15), 4.88 (1H, t, J=4.9 Hz, H-20), 4.94(1H, dd, J=8.1 & 9.9 Hz, H-2'), 5.07 (1H, br, H-3), 5.42 (1H, d, J=10.3Hz, H-13), 5.60 (1H, bd, J=15.8Hz, H-10), 6.50 (1H, d, J=15.8 Hz, H-11),

FAB-MS: 1096 (M+H)⁺

Example 23 2',4"-Di-O-acetyl-2,3-dehydro-3,4'-dideoxy-4'-iodo desmycosin9,20-bis(ethyleneacetal)

162 μl (2.28 mmol) of dimethyl sulfoxide and 27.4 mg (0.684 mmol) ofsodium hydride were added to 6 ml of toluene to conduct the reaction atroom temperature for 10 min. The resultant solution was cooled with ice,to which 500 mg (0.456 mmol) of 3,2',4"-tri-O-acetyl4'-deoxy-4'-iododesmycosin 9,20-bis(ethyleneacetal) was added and the resultant mixturewas stirred at room temperature for 2 h. 9.1 mg (0.228 mmol) of sodiumhydride was added to the mixture to conduct the reaction at roomtemperature for 14 h. 10 ml of toluene was added to the reaction liquid.After washing with water followed by drying over anhydrous sodiumsulfate, the organic layer was concentrated under reduced pressure anddried in vacuo to obtain 481 mg of an amorphous solid mainly comprisingthe intended compound which was positive in sulfuric acid color reactionat Rf 0.69 on silica gel TLC with toluene/acetone (4/1) developer.

UV(MeOH) λ max: 216 nm

IR(KBr) ν max: 2975,2936,2880,1750,1717,1373,1233,1171,1090,1049 cm⁻¹

NMR(CDCl₃): (only main peaks)

ε: 0.95 (3H, t, J=7.3 Hz, H-17), 1.17 (3H, d, J=6.6 Hz, H-6"), 1.53 (3H,d, J=5.1 Hz, H-6'), 1.69 (3H, s, H-22), 2.04 (3H, s, OCOCH₃), 2.11 (3H,s, OCOCH₃), 2.43 (6H, s, N (CH₃)₂ -3'), 3.05 (1H, dd, J=2.9 & 8.1 Hz,H-2"), 3.48 (3H, s, OCH₃ -2"), 3.52 (3H, s, OCH₃ -3"), 4.62 (1H, d,J=8.1 Hz, H-1"), 5.33 (1H, d, J=10.3 Hz, H-13), 5.47 (1H, d, J=15.4 Hz,H-10), 5.55 (1H, d, J=15.4 Hz, H-2), 6.24 (1H, d, J=15.4 Hz, H-11), 6.69(1H, dd, J=15.4 & 9.5 Hz, H-3),

FAB-MS: 1036 (M+H)⁺

Example 24 3,4'-Dideoxy desmycosin 9,20-bis(ethyleneacetal)

470 mg (0,454 mmol) of2',4"-di-O-acetyl-2,3-dehydro-3,4'-dideoxy-4'-iodo desmycosin9,20-bis(ethyleneacetal) was dissolved in 6 ml of methanol. 200 mg (1.45mmol) of potassium carbonate was added to the solution and then asuspension of 400 mg (wet weight) (0.3 ml) of a Raney nickiel (NDT-65; aproduct of Kawaken Fine Chemicals Co., Ltd.) in 1 ml of methanol wasadded thereto.After conducting the catalytic reduction under a hydrogenpressure of 3.5 kg/cm² for 2 h, the catalyst was filtered off throughCelite. The mother liquid was left to stand overnight and thenconcentrate under reduced pressure. 20 ml of ethyl acetate and 20 ml ofwater were added to the residue to divide it into layers.The organiclayer was washed with 20 ml of saturated aqueous common salt solutionand then dried over anhydrous sodium sulfate. The organic layer wasconcentrated under reduced pressure to obtain 423 mg of a residue, whichwas subjected to silica gel chromatography (40 g) withchloroform/methanol (25/1) eluent. A fraction which was positive insulfuric acid color reaction at Rf 0.45 on silica gel TLC withchloroform/methanol (5/1) developer was taken to obtain 285 mg (yield:76%) of a colorless amorphous solid.

UV(MeOH) λ max: 234 nm

IR(KBr) ν max: 3466,2971,2936,2880,1730,1379,1167,1082 cm⁻¹

NMR(CDCl₃): (only main peaks)

ε: 0.93 (3H, t, J=7.3 Hz, H-17), 1.23 (3H, d, J=6.2 Hz, H-6'), 1.26 (3H,d, J=6.6 Hz, H-6'), 1.72 (3H, s, H-22), 2.28 (6H, s, N (CH₃)₂ -3'), 2.86(1H, m, H-14), 3.48 (3H, s, OCH₃ -2'), 3.61 (3H, s, OCH₃ -3"), 4.28(1H,d, J=7.3 Hz, H-1'), 4.54 (1H, d, J=7.7 Hz, H-1"), 4.91 (1H, m, H-15),5.01 (1H, br, H-20), 5.42 (1H, d, J=10.6 Hz, H-13), 5.60 (1H, d, J=15.8Hz, H-10), 6.39 (1H, d, J=15.8 Hz, H-11),

FAB-MS: 828 (M+H)⁺

Example 25 2'-O-Acetyl-3,4'-dideoxy desmycosin 9,20-bis(ethyleneacetal)

285 mg of 3,4'-dideoxy desmycosin 9,20-bis(ethyleneacetal) was dissolvedin 3.0 ml of ethyl acetate. 51.4 μl of acetic anhydride was added to thesolution, and the reaction was conducted at room temperature for 3 h. 10ml of ethyl acetate was added to the reaction liquid.After washing with10 ml of 5% aqueous sodium hydrogencarbonate solution and 10 ml of 20%aqueous common salt solution, the organic layer was dried over anhydroussodium sulfate and dryed to solid under reduced temperature to obtain300 mg of the intended compound which was Dositive in sulfuric acidcolor reaction at Rf 0.44 on silica gel TLC with chloroform/methanol(10/1) developer.

UV(MeOH) λ max: 235 nm

IR(KBr) ν max: 3476,2973,2938,2882,1744,1373,1238,1167,1061,961 cm⁻

NMR(CDCl₃): (only main peaks)

ε: 0.82 (3H, bd, J=5.5 Hz, H-18), 0.92 (3H, t, J=7.3 Hz, H-17), 1.00(3H, d, J=6.6 Hz, H-21), 1.23 (3H, d, J=6.2 Hz, H-6'), 1.26 (3H, d,J=6.2 Hz, H-6"), 1.35 (114, m, H-4'a), 1.71 (1H, m, H-4' b) 1.73 (3H, d,J=1.1 Hz, H-22), 2.04 (3H, s, OCOCH₃ -2'), 2.26(6H, s, N (CH₃)₂ -3'),2.68 (1H, ddd, J=12.3 & 10.4 & 4.4 Hz, H-3"), 3.18 (1H, br, H-4"), 3.48(3H, s, OCH₃ -2"), 3.61 (3H, s, OCH₃ -3") 4.31 (1H, d, J=7.7 Hz, H-1'),4.55 (1H, d, J=7.7 Hz, H-1"), 4.80 (1H, dd, J=10.4 & 7.7 Hz, H-2'), 4.90(1H, m, H-15), 4.95 (1H, bt, J=5.1 Hz, H-20), 5.42 (1H, d, J=10.6 Hz,H-13), 5.62 (1H, d, J=15.8 Hz, H-10), 6.36 (1H, d, J=15.8 Hz, H-11)

FAB-MS: 870 (M+H)⁺

Example 26 3,2'-Di-O-acetyl-4"-O-isovaleryldemycinosyltylosin

48.4 g (55.7 mmol) of 3-O-acetyl-4"-O-isovaleryl demycinosyltylosin wasdissolved in 200 ml of ethyl acetate. 6.3 ml (66.9 mmol) of aceticanhydride was added to the solution, and the reaction was conducted atroom temperature for 2 h. The reaction liquid was washed with 200 ml of5% aqueous sodium hydrogencarb0nate solution and 200 ml of 20% aqueouscommon salt solution, dried over anhydrous sodium sulfate and dried tosolid under reduced pressure to obtain 50.7 g of the intended compoundwhich was positive in sulfuric acid color reaction at Rf 0.66 on silicagel TLC with toluene/acetone (1/1) developer.

UV(MeOH) λ max: 282 nm

IR(KBr) ν max: 2973,2940,1740,1595,1373,1235,1169,1057,1028 cm⁻¹

NMR(CDCl₃): (only main peaks)

ε:0.92(3H,t,J=7,3 Hz,H-17) 0.98(6H,d,J=6,6 Hz, dimethyl of isovaleryl)1.84 (3H, s, H-22), 2.06 (3H, s, OCOCH₃ -2'), 2.13 (3H, s, OCOCH₃ -3),2.41 (6H, s, N (CH₃)₂ -3'), 4.24 (1H, d, J=7.7 Hz, H-1'), 4.62 (1H, d,J=10.3 Hz, H-4"), 5.01 (1H, dd, J=7.7 & 10.6 Hz, H-2'), 5.06 (1H, d,J=3.3 Hz, H-1"), 5.13 (1H, d, J=10.6 Hz, H-3), 5.90 (1H, d, J=10.3 Hz,H-13), 6.32 (1H, d, J=15.8 Hz, H-10), 7.40 (1H, d, J=15.8 Hz, H-11),9.60 (1H, s, H-20)

FAB-MS: 910 (M+H)⁺

Example 27 3,2'-Di-O-acetylmycaminosyltylonolide

450 ml of water was added to 50.7 g (55.7 mmol) of3,2'-di-O-acetyl-4"-O-isovaleryldemycinosyltylosin, and the resultantmixture was stirred. An aqueous solution prepared by diluting 8.9 ml(167 mmol) of concentrated sulfuric acid with 50 ml of water was pouredtherein to dissolve the starting material. The temperature was thenelevated to 50° C. 0.5 h after, the reaction liquid was cooled to 15° C.and washed with 300 ml of ethyl acetate three times. The aqueous layerwas controlled at pH 5.8 with 20% aqueous sodium carbonate solution.After extraction with 300 ml of ethyl acetate twice, the extract wasdried over anhydrous sodium sulfate and then dried to solid underreduced pressure to obtain 29.1 g of the intended compound which waspositive in sulfuric acid color reaction on silica gel TLC at Rf 0.33with toluene/acetone (2/1) developer.

UV (MeOH) λ max: 282 nm

IR (KBr) ν max: 2973,2938,1738,1593,1373,1236,1059 cm⁻

NMR(CDCl₃): (only main peaks)

ε:0.92 (3 H, t, J=7.3Hz, H-17), 0.99 (3H, d, J:6.6 Hz, H-18), 1.22(3H,d, J:6.6 Hz, H-21), 1.28 (3H, d, J=6.2 Hz, H-6'), 1.84(3H, d, J=0.7 Hz,H-22), 2.06 (3H, s, OCOCH₃ -2'), 2.15(3H, s, OCOCH₃ -3), 2.40 (6H, s, N(CH₃)₂ -3'), 2.93(1H, m, H-14), 3.03 (1H, t, J=9.5 Hz, H-4'), 3.50(1H,bd, J=8.8 Hz, H-5), 3.67 (1H, dd, J=7.0 & 10.6 Hz, H-23a), 3.72(1H, dd,J=4.4 & 10.6 Hz, H-23b), 4.29 (1H, d, J=7.7 Hz, H-1'), 4.79(1H, m,H-15), 4.99 (1H, dd, J=7.7 & 10.6 Hz, H-2'), 5.14 (1H, bd, J=10.6 Hz,H-10), 5.91 (1H, d, J=10.3 Hz, H-13), 6.31 (1H, d, J=15.8 Hz, H-10),7.40 (1H, d, J=15.4 Hz, H-11), 9.61 (1H, s, H-20)

FAB-MS: 682 (M+H)⁺

Example 28 3,2'-Di-O-acetylmycaminosyltylonolide9,20-bis(ethyleneacetal)

9.74 g (51.2 mmol) of p-toluenesulfonic acid monohydrate was added to100 ml of toluene, and the mixture was heated to distill off about 50 mlof toluene. After dehydration, the solution was cooled to or below, towhich 28.4 ml (171 mmol) of ethyl orthoacetate and 23.8 ml (427 mmol) ofethylene glycol were added. The resultant solution was added to a cooledsolultion of 29.1 g (42.7 mmol) of 3,2'-di-O-acetylmycaminosyltylonolidein 110 ml of toluene. The resultant mixture was stirred at roomtemperature for 1.5 h, then the temperature was gradually elevated to50° C., and the reaction was conducted for 1 h. The reaction liquid waswashed with 150 ml of 5% aqueous sodium hydrogencarbonate solution and150 ml of 10% aqueous common salt solution, dried over anhydrous sodiumsulfate and dried to solid under reduced pressure to obtain 30.48 g ofthe intended compound which was positive in sulfuric acid color reactionat Rf 0.55 on silica gel TLC with toluene/acetone (1/1) developer.

UV(MeOH) λ max: 235 nm

IR(KBr) ν max: 2975,2940,2882,1742,1373,1238,1182,1055 cm⁻¹

NMR(CDCl₃): (only main peaks)

ε:0.85 (3H, br, H-18), 0.92 (3H, t, J=7.3 Hz, H-17), 1.00 (3H, d, J=6.6Hz, H-21), 1.31 (3H, d, J=6.2 Hz, H-6'), 1.77 (3H, d, J=1.1 Hz, H-22),2.05 (3H, s, OCOCH₃ -2'), 2.13 (3H, s, OCOCH₃ -3), 2.39 (6H, s, N (CH₃)₂-3'), 2.86 (1H, m, H-14), 3.05 (1H, t, J=9.5 Hz, H-4'), 3.57 (1H, dd,J=8.1 & 10.6 Hz, H-23a), 3.64 (1H, m, H-5), 3.69 (1H, dd, J=4.4 & 10.6Hz, H-23b), 4.29 (1H, br, H-1'), 4.76 (1H, m, H-15), 4.91 (1H, m, H-20),5.03 (1H, dd, J=7.7 & 10.6 Hz, H-2'), 5.06 (1H, br, H-3), 5.38 (1H, bd,J=10.6 Hz, H-13), 5.69 (1H, bd, J=15.4 Hz, H-10) 6.54 (1H, bd, J=15.4Hz, H-11)

FAB-MS: 770 (M+H)⁺

Example 29 3,2'-Di-O-acetylmycaminosyltylonolide9,20-bis(ethyleneacetal)

27.9 g (0.147 mol) of p-toluenesulfonic acid monohydrate was added to250 ml of toluene, and the mixture was heated to distill and dehydrated.The solution was cooled to 5° C. or below, to which 81.2 ml (0.488 mol)of ethyl orthoacetate and 68.1 ml (1.22 mmol) of ethylene glycol wereadded. The resultant solution was added to a cooled solultion of 111.1 g(0.122 mol) of 3,2'-di-O-acetyl-4"-O-isovaleryldemycinosyltylosin in 400ml of toluene. The reaction liquid was gradually elevated to 50° C., andthe reaction was conducted for 1.5 h. The reaction liquid was washedwith 500 ml of 5% aqueous sodium hydrogencarbonate solution and 500 mlof 10% aqueous common salt solution twice, dried over anhydrous sodiumsulfate and dried to solid under reduced pressure. The resultant residuewas purified by silica gel column chromatography with toluene/acetone(3/1) developer to obtain 75.2 g of the intended compound which was thesame as that of Example 28 in the form of an amorphous solid.

Example 303,2'-Di-O-acetyl-23-O-t-butyldimethylsilylmycaminosyltylonolide9,20-bis(ethyleneacetal)

30.3 g (39.3 mmol) of 3,2'-di-O-acetylmycaminosyltylonolide9,20-bis(ethyleneacetal) was dissolved in 150 ml of dimethylformamide.4.04 g (59.4 mmol) of imidazole was added to the solution, and theresultant mixture was cooled to 0° C. 6.56 g (43.5 mmol) oft-butyldimethylsilyl chloride was added to the mixture under stirringand the reaction was conducted at room temperature for 2 h. 300 ml oftoluene was added to the reaction liquid. After washing with 300 ml of5% aqueous sodium hydrogencarbonate solution twice and 150 ml of waterfollowed by drying over anhydrous sodium sulfate, the organic layer wasdried to solid under reduced pressure to obtain 34.6 g of the intendedcompound which was positive in sulfuric acid color reaction at Rf 0.55on silica gel TLC with toluene/acetone (2/1) developer.

UV(MeOH) λ max: 235 nm

IR(KBr) ν max: 2936,2884,1746,1373,1236,1084,1055,837,777 cm⁻

NMR(CDCl₃): (only main peaks)

ε:0.85(3H,br,H-18) 0.87 (9H, s,t-butyl of t-butyldimethylsilyl) 0.90(3H, t, J=7.3 Hz, H-17), 1.00 (3H, d, J=6.6 Hz, H-21), 1.31 (3H, d,J=6.2 Hz, H-6'), 1.72 (3H, d, J=0.7 Hz, H-22, 2.05 (3H, s, OCOCH₃ -2'),2.12 (3H, s, OCOCH₃ -3), 2.39 (SH, s, N (CH₃)₂ -3'), 3.04 (1H, t, J=9.5Hz, H-4'), 4.29 (1H, bd, J=6.2 Hz, H-1'), 4.83 (1H, m, H-15), 4.91 (1H,t, J=4.8 Hz, H-20), 5.03 (1H, dd, J=7.7 & 10.6 Hz, H-2') 5.06 (1H, br,H-3), 5.37 (1H, d, J=10.3 Hz, H-13), 5.63 (1H, bd, J=15.4 Hz, H-10),6.50 (1H, hal, J=15.4 Hz, H-11)

FAB-MS: 884 (M+H)⁺

Example 312'-O-Acetyl-23-O-t-butyldimethylsilyl-2,3-dehydro-3-deoxymycaminosyltylonolide9,20-bis (ethyleneacetal)

2.34 g (58.6 mmol) of sodium hydride (60% in oil) was added to a mixedsolvent comprising 100 ml of toluene and 13.9 ml (195 mmol) of dimethylsulfoxide, and the resultant mixture was stirrred for 10 min. Thereaction liquid was cooled to 0° C., and a solution of 34.5 g (39.0mmol) of 3,2'-di-O-acetyl-23-O-t-butyldimethylsilylmycaminosyltylonolide 9,20-bis(ethyleneacetal) in 70 ml of toluene was addeddropwise thereto. After conducting the reaction at that temperature for1 h, 100 ml of water was added, and the mixture was controlled at pH 6with 1 N-hydrochloric acid to divide it into layers. The organic layerwas washed with 100 ml of 10% aqueous common salt solution, dried overanhydrous sodium sulfate and concentrated under reduced pressure toobtain 32.1 g of the intended compound which was positive in sulfuricacid color reaction at Rf 0.46 on silica gel TLC with toluene/acetone(3/1) developer.

UV(MeOH) λ max: 217 nm

IR(KBr) ν max: 2936,2881,1750,1717,1373,1232,1080,1057,837,777 cm⁻¹

NMR(CDCl₃): (only main peaks)

ε:0.89(9H,s,t-butyl of t-butyldimethylsilyl) 0.95 (3H, t, J=7.3Hz,H-17), 1.34 (3H, d, J=6.2 Hz, H-6'), 1.71 (314, d, J=0.7 Hz, H-22), 2.06(3H, s, OCOCH₃ -2'), 2.44 (6H, s, N (CH₃)₂ -3'), 3.11 (1H, t, J=9.2 Hz,H-4'), 4.44 (1H, d, J=7.3 Hz, H-1'), 4.90 (1H, m, H-15), 4.96 (1H, m,H-20), 5.06 (1H, dd, J=7.3 & 10.6 Hz, H-2'), 5.29 (1H, d, J=10.3 Hz,H-13), 5.51 (1H, d, J=15.8 Hz, H-10), 5.55 (1H, d, J=15.4 Hz, H-2), 6.25(1H, d, J=15.8 Hz, H-11), 6.70 (1H, dd, J=9.5 & 15.4 Hz, H-11)

FAB-MS: 824 (M+H)⁺

Example 322'-O-Acetyl-23-O-t-butyldimethylsilyl-2,3-dehydro-3,4'-dideoxy-4'-iodomycaminosyltylonolide9,20-bis(ethyleneacetal)

31.8 g (38.6 mmol) of2'-O-acetyl-23-O-t-butyldimethylsilyl-2,3-dehydro-3-deoxymycaminosyltylonolide9,20-bis(ethyleneacetal) was dissolved in 230 ml of methyl ethylketone.10.8 ml (77.3 mmol) of triethylamine was added to the solution.Then a solution of 3.9 ml (50.2 mmol) of methanesulfonyl chloride in 15ml of methyl ethyl ketone was added to the resultant mixture undercooling with ice. The reaction was conducted at that temperature for 1 hto obtain a mesylated compound[2'-O-acetyl-23-O-t-butyldimethylsilyl-2,3-dehydro-3-deoxy-4'-O-methanesulfonylmycaminosytylonolide9,20-bis(ethyleneacetal)]. 17.4 g (116 mmol) of sodium iodide was addedto the reaction liquid, and the temperature was elevated. After heatingunder reflux for 3 h to conduct the iodination, the reaction liquid wasconcentrated. 250 ml of toluene and 250 ml of water were added to theconcentrate to divide it into layers. After washing with 250 ml of 10%sodium thiosulfate and 250 ml of 10% aqueous common salt solutionfollowed by drying over anhydrous sodium sulfate, the organic layer wasconcentrated to dryness under reduced pressure to obtain 36.1 g of theintended compound which was positive in sulfuric acid color reaction atRf 0.51 on silica gel TLC with toluene/acetone (10/1) developer.

2'-O-Acetyl-23-O-t-butyldimethylsilyl-2,3-dehydro-3-deoxy-4'-O-methanesulfonylmycaminosyltylonolide9,20-bis(ethyleneacetal):

Rf: 0.55[toluene/acetone(6/1) ]

NMR(CDCl₃ ): (only main peaks)

ε:0.89 (9H, s, t-butyl of t-butyldimethylsilyl) 0.95 (3H, t, J=7.3 Hz,H-17), 1.38 (3H, d, J=6.2 Hz, H-6'), 1.71 (3H, s, H-22), 2.06 (3H, s,OCOCH₃ -2'), 2.40 (6H, s, N (CH₃)₂ -3'), 2.89 (1H, t, J=10.3 Hz, H-3'),3.11 (3H, s, OSO₂ CH₃ -4'), 4.24 (1H, t, J=9.5 Hz, H-4'), 4.42 (1H, d,J=10.3 Hz, H-1'), 5.08 (1H, dd, J=7.7 & 10.3 Hz, H-2'), 5.29 (1H, d,J=10.3 Hz, H-13), 5.50 (1H, d, J=15.8 Hz, H-10), 5.55 (1H, d, J=15.4 Hz,H-2), 6.24 (1H, d, J=15.8 Hz, H-11), 6.88 (1H, dd, J=9.5 & 15.4 Hz, H-3)

FAB-MS: 902 (M+H)⁺

Intended compound:

UV(MeOH) λ max: 217 nm

IR(KBr) ν max: 2936,2882,1752,1715,1373,1231,1101,1051,837,777 cm⁻

NMR(CDCl₃ ): (only main peaks)

ε:0.89 (9H, s ,t-butyl of t-butyldimethylsilyl) 0.95 (3H, t, J=7.3 Hz,H-17), 1.53 (3H, d, J=5.5 Hz, H-6'), 1.71 (3H, d, J=0.7 Hz, H-22), 2.05(3H, s, OCOCH₃ -2'), 2.43 (6H, s, N (CH₃)₂ -3'), 2.84 (1H, m, H-3'),4.42 (1H, d, J=7.7 Hz, H-1'), 4.96 (1H, dd, J=7.7 & 9.9 Hz, H-2'),5.29(1H, d, J=10.3 Hz, H-13), 5.50 (1H, d, J=15.8 Hz, H-10), 5.55(1H, d,J=15.4 Hz, H-2), 6.25 (1H, d, J=15.8 Hz, H-11), 6.69 (1H, dd, J=9.5 &15.4 Hz, H-3)

FAB-MS: 934 (M+H)⁺

Example 333,2'-di-O-Acetyl-23-O-t-butyldimethylsilyl-4'-O-methanesulfonylmycaminosyltylonolide9,20-bis(ethyleneacetal)

50.0 mg (0.0565 mmol) of3,2'-di-O-acetyl-23-O-t-butyldimethylsilylmycaminosyltylonolide9,20-bis(ethyleneacetal) was dissolved in 1 ml of methyl ethylketone.35.4 μl (0.254 mmol) of triethylamine was added to the solution.Then a solution of 17.1 μl (0.220 mmol) of methanesulfonyl chloride in50 ml of methyl ethyl ketone was added to the resultant mixture undercooling with ice. The resultant mixture was stirred at that temperaturefor 1 h, and 10 ml of chloroform was added to the reaction liquid. Afterwashing with 10 ml of saturated aqueous sodium hydrogencarbonatesolution and 10 ml of saturated aqueous common salt solution twice, theorganic layer was concentrated to dryness under reduced pressure toobtain 53.9 mg of the intended compound which was positive in sulfuricacid color reaction at Rf 0.57 on silica gel TLC with toluene/acetone(5/1) developer.

NMR(CDCl₃): (only main peaks)

ε:0.84(3H,br,H-18) 0.87(9H,s,t-butyl of t-butylsilyl) 0.90 (3H, t, J=7.3Hz, H-17), 0.99 (3H, d, J=6. 6 Hz, H-21), 1.36 (3H, d, J=5.9 Hz, H-6'),1.72 (3H, s, H-22), 2.06 (3H, s, OCOCH₃ -2'), 2.11 (3H, s, OCOCH₃ -3),2.39 (6H, s, N (CH₃)₂ -3'), 2.73 (1H, m, H-14), 3.10 (3H, s, OSO₂ CH₃-4'), 3.43 (1H, m, H-5'), 4.22 (1H, t, J=9.5 Hz, H-4'), 5.37 (1H, d,J=10.3 Hz, H-13), 5.63 (1H, d, J=16.1 Hz, H-10), 6.49 (1H, d, J=16.1 Hz,H-11)

FAB-MS: 962 (M+H)⁺

Example 343,2'-di-O-Acetyl-23-O-t-butyldimethylsilyl-4'-deoxy-4'-iodomycaminosyltylonolide9,20-bis(ethyleneacetal):

266.1 mg (0.301 mmol) of3,2'-di-O-acetyl-23-O-tbutyldimethylsilylmycaminosyltylonolide9,20-bis(ethyleneacetal) was dissolved in 2 ml of methyl ethyl ketone.62.9 μl (0.452 mmol) of triethylamine was added to the solution. Then asolution of 28.0 μl (0.361 mmol) of methanesulfonyl chloride in 70 μl ofmethyl ethyl ketone was added to the resultant mixture under coolingwith ice. The resultant mixture was stirred at that temperature for 0.5h to complete the mesylation reaction. 135.4 mg (0.903 mmol) of sodiumiodide was added to the reaction liquid, and the temperature waselevated. After heating under reflux for 0.5 h to conduct theiodination, 10 ml of chloroform was added to the reaction liquid. Afterwashing with 10 ml of saturated aqueous sodium hydrogencarbonatesolution and 10 ml of saturated aqueous common salt solution twicefollowed by drying over anhydrous sodium sulfate, the organic layer wasconcentrated under reduced pressure and then the residue was purified bysilica gel column chromatography with toluene/ethyl acetate (12/1)developer to obtain 210 mg (yield: 70%) of the intended compound whichwas positive in sulfuric acid color reaction at Rf 0.57 on silica gelTLC with toluene/acetone (10/1) developer.

UV(MeOH) λ max: 235 nm

IR(KBr) ν max: 2934,2882,1744,1372,1233,1179,1103,1049 cm⁻

NMR (CDCl₃): (only main peaks)

ε: 0.87 (9H, s, t-butyl of t-butyldimethylsilyl) 0.90 (3H, t, J=7.3 Hz,H-17), 0.99 (3H, d, J=6.6 Hz, H-21), 1.51 (3H, d, J=5.9 Hz, H-6'), 1.72(3H, s, H-22), 2.05 (3H, s, OCOCH₃ -2'), 2.12 (3H, s, OCOCH₃ -3), 2.42(6H, s, N (CH₃)₂ -3'), 4.28 (1H, d, J=7.3 Hz, H-1'), 5.07 (1H, br, H-3),5.37 (1H, d, J=11.0 Hz, H-13), 5.62 (1H, d, J=15.4 Hz, H-10), 6.50 (1H,d, J=15.4 Hz, H-11),

FAB-MS: 994 (M+H)⁺

Example 352'-O-acetyl-23-O-t-butyldimethylsilyl-2,3-dehydro-3,4'-dideoxy-4'-iodomycaminosyltylonolide9,20-bis(ethyleneacetal)

50.0 mg (0.0503 mmol) of3,2'-di-O-acetyl-23-O-t-butyldimethylsilyl-4'-deoxy-4'-iodomycaminosyltylonolide9,20-bis(ethyleneacetal) was dissolved in a mixed solvent comprising 0.5ml of toluene and 35.7 μl (0.503 mmol) of dimethyl sulfoxide. 5.4 mg(0.226 mmol) of sodium hydride (60% in oil) was added to the solution,and the resultant mixture was stired for 20 h. 10 ml of ethyl acetatewas added to the reaction liquid. After washing with 10 ml of water and10 ml of saturated aqueous common salt solution twice, the organic layerwas dried over anhydrous sodium sulfate and then concentrated underreduced pressure. The residue was purified by a dispensing silica gelTLC with toluene/acetone (10/1) developer to obtain 30 mg of theintended compound which was the same as that obtained in Example 32.

Example 36 23-O-t-butyldimethylsilyl-3,4'-dideoxymycaminosyltylonolide9,20-bis(ethyleneacetal)

35.9 g (38.4 mmol) of2'-O-acetyl-23-O-t-butyldimethylsilyl2,3-dehydro-3,4'-dideoxy-4'-iodomycaminosylthylonolide9,20-bis(ethyleneacetal) was dissolved in 175 ml of methanol. 7.95 g(57.5 mmol) of potassium carbonate was added to the solution and then asuspension of 20 g a Raney nickiel (NDT-65; a product of Kawaken FineChemicals Co., Ltd.) in 30 ml of methanol was added thereto. Afterconducting the catalytic reduction under a hydrogen pressure of 3.5kg/cm² for 2 h, the catalyst was filtered off through Celite. Thefiltrate was concentrated under reduced pressure. 200 ml of ethylacetate was added to the residue. After washing with 200 ml of 20%aqueous common salt solution twice followed by drying over anhydroussodium sulfate and drying to solid under reduced pressure, 28.0 g of theintended compound was obtained, which was positive in sulfuric acidcolor reaction at Rf 0.45 on silica gel TLC with chloroform/methanol(10/1) developer.

UV(MeOH) λ max: 235 nm

IR(KBr) ν max: 2938,2884,1734,1169,1111,1049,837,777 cm ⁻¹

NMR(CDCl₃): (only main peaks)

ε:0.88(9H,s,t-butyl of t-butyldimethylsilyl) 0.92 (3H, t, J=7.3 Hz,H-17), 0.98 (3H, d, J=6.6 Hz, H-18), 1.02 (3H, d, J=7.0 Hz, H-21), 1.23(3H, d, J=6.2 Hz, H-6'), 1.74 (3H, d, J=1.1 Hz, H-22), 2.27 (6H, s, N(CH₃)₂ -3'), 3.26 (1H, dd, J=7.3 & 9.9 Hz, H-2'), 4.28 (1H, d, J=7.3 Hz,H-1'), 4.91 (1H, m, H-15), 5.01 (1H, m, H-20), 5.37 (1H, d, J=10.3 Hz,H-13), 5.61 (1H, d, J=15.8 Hz, H-10), 6.39 (1H, d, J=15.8 Hz, H-11)

FAB-MS: 768 (M+H)⁺

Example 37 3,4'-Dideoxymycaminosyltylonolide

27.7 g (36.0 mmol) of23-O-t-butyldimethylsilyl-3,4'-dideoxymycaminosyltylonolide9,20-bis(ethyleneacetal) was dissolved in 150 ml of tetrahydrofuran. 300ml of 1 N-hydrochloric acid was added to the solution, and the resultantmixture was stirred at room temperature for 1.5 h to conduct thehydrolysis reaction. 300 ml of water was added to the reaction liquid,and the resultant aqueous solution was washed with 150 ml of methylenechloride twice. pH of the aqueus layer was controlled at 6.0. Afterextraction with 300 ml of methylene chloride, the aqueous layer wasagain controlled at pH 6.0 and extracted with 300 ml of methylenechloride. The organic layers were combined together, washed with 300 mlof 20% aqueous common salt solution and dried over anhydrous sodiumsulfate. The organic layer was dried to solid under reduced pressure toobtain 9.46 g of the intended compound.

This product had the same physicochemical properties as those of3,4'-dideoxymycaminosyltylonolide described in Journal of Antibiotics(1992).

Industrial Applicability

3,4'-Dideoxymycaminosyltylonolide which can be produced by the processof the present invention is a substance having an antimicrobialactivity-on Gram-positive and Gram-negative microorganisms in a broadrange as described in J.P. KOKAI No. Hei 2-275894. In particular, it isuseful as an antimicrobial agent, since it has an excellent effect ofprevention from infection.

What is claimed is:
 1. A compound of the following formula: ##STR10##wherein A represents a carbonyl group which is not protected orprotected by dimethylacetal, diethylacetal, diethylthioacetal,ethyleneacetal or propyleneacetal;B represents an aldehyde group whichie not protected or protected by dimethylacetal, diethylacetal,diethylthioacetal, ethyleneacetal or propyleneacetal; R¹ represents agroup of the following formula: ##STR11## (Z being CHR⁴ or C═O, and R⁴being a hydroxyl group which is not protected or protected byt-butyldimethylsilyl, dimethylhexylsilyl, trimethylsilyl, triethylsilyl,tri(t-butyl) silyl, trityl, tetrahydropyranyl, tetrahydrofuranyl, allyl,fluoroacetyl, difluoroacetyl, trifluoroacetyl, chloroacetyl,dichloroacetyl, trichloroacetyl, bromoacetyl, dibromoacetyl,methoxyacetyl, ethoxyacetyl, phenoxyacetyl, benzoyl, benzyl,methoxymethyl or benzyloxycarbonyl group) R² represents a hydrogen atomor acyl group selected from the group consisting of formyl, acetyl,propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl,benzoyl, toluoyl, xyloyl groups, phenylacetyl, phenylpropionyl andphenylhexanoyl groups; W represents a hydrogen atom or sulfonyloxy grouprepresented by the formula: --OSO₂ R³ wherein R³ represents methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl,1-methybutyl, 2-methylbutyl, neopentyl, trifluoromethyl,2-oxo-10-bornanyl, phenyl, p-methoxyphenyl, p-nitrophenyl,p-fluorophenyl, o,p-difluorophenyl, pichlorophenyl, m-chlorophenyl,o-chlorophenyl, o,p-dichlorophenyl, p-bromophenyl, p-methylphenyl,m-methylphenyl, o,p-dimethylphenyl, m,p-dlmethylphenyl, naphthyl,benzyl, p-nitrobenzyl, o,p-dinitrobenzyl, p-chlorobenzyl,m-chlorobenzyl, p-methylbenzyl, m-methylbenzyl, o-methylbenzyl,o,p-dimethylbenzyl, p-methoxybenzyl or p-fluorobenzyl groups; Yrepresents a halogen atom or sulfonyloxy group represented by theformula: --Oso₂ R³ wherein R³ represents methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl, pentyl, 1-methybutyl,2-methylbutyl, neopentyl, trifluoromethyl, 2-oxo-10-bornanyl, phenyl,p-methoxyphenyl, p-nitrophenyl, p-fluorophenyl, o,p-difluorophenyl,p-chlorophenyl, m-chlorophenyl, o-chlorophenyl, o,p-dichlorophenyl,p-bromophenyl, p-methylphenyl, m-methylphenyl, o,p-dimethylphenyl,m,p-dimethylphenyl, naphthyl, benzyl, p-nitrobenzyl, o,p-dinitrobenzyl,p-chlorobenzyl, m-chlorobenzyl, p-methylbenzyl, m-methylbenzyl,o-methylbenzyl, o,p-dimethylbenzyl, p-methoxybenzyl or p-fluorobenzylgroups; and broken line "-------" represents a single bond.
 2. Acompound of the following formula: ##STR12## wherein A represents acarbonyl group which is not protected or protected by dimethylacetal,diethylacetal, diethylthioacetal, ethyleneacetal or propyleneacetal;Brepresents an aldehyde group which is not protected or protected bydimethylacetal, diethylacetal, diethylthioacetal, ethyleneacetal orpropyleneacetal; R¹ represents a group of the following formula:##STR13## (Z being CHR⁴ or C═O, and R⁴ being a hydroxyl group which isnot protected or protected by t-butyldimethylsilyl, dimethylhexylsilyl,trimethylsilyl, triethylsilyl, tri(t-butyl)silyl, trityl,tetrahydropyranyl, tetrahydrofuranyl, allyl, fluoroacetyl,difluoroacetyl, trifluoroacetyl, chloroacetyl, dichloroacetyl,trichloroacetyl, bromoacetyl, dibromoacetyl, methoxyacetyl,ethoxyacetyl, phenoxyacetyl, benzoyl, benzyl, methoxymethyl orbenzyloxycarbonyl group); R² represents a hydrogen atom or acyl groupselected from the group consisting of formyl, acetyl, propionyl,butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, benzoyl,toluoyl, xyloyl groups, phenylacetyl, phenylpropionyl and phenylhexanoylgroups; W represents a hydrogen atom or a alkanoyloxy group which isselected from the group consisting of linear or branched alkanoyl groupshaving 1 to 6 carbon atoms; Y represents a halogen atom or sulfonyloxygroup represented by the formula: --OSO₂ R³ wherein R³ representsmethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl,1-methybutyl, 2-methylbutyl, neopentyl, trifluoromethyl,2-oxo-10-bornanyl, phenyl, p-methoxyphenyl, p-nitrophenyl,p-fluorophenyl, o,p-difluorophenyl, p-chlorophenyl, m-chloropheny1,o-chlorophenyl, o,p-dichlorophenyl, p-bromophenyl, p-methylphenyl,m-methylphenyl, o,p-dimethylphenyl, m,p-dimethylphenyl, naphthyl,benzyl, p-nitrobenzyl, o,p-dinitrobenzyl, p-chlorobenzyl,m-chlorobenzyl, p-methylbenzyl, m-methylbenzyl, o-methylbenzyl,o,p-dimethylbenzyl, p-methoxybenzyl or p-fluorobenzyl group; and brokenline "-------" represents a double bond when W is hydrogen atom and asingle bond when W is an alkanoyloxy group selected from the groupconsLsting of linear or branched alkanoyl groups having 1 to 6 carbonatoms; with the proviso that when Z is CHR⁴ and R² is said hydrogenatom, Y is said sulfonyloxy group.
 3. A compound of the followingformula: ##STR14## wherein A represents a carbonyl group which is notprotected or protected by dimethylacetal, diethylacetal,diethylthioacetal, ethyleneacetal or propyleneacetal;B represents analdehyde group which is not protected or protected by dimethylacetal,diethylacetal, diethylthioacetal, ethyleneacetal or propyleneacetal; R¹represents a hydroxyl group which is not protected or protected byt-butyldimethylilyl, dimethylhexylsilyl, trimethylsilyl, triethylsilyl,tri(t-butyl) silyl, trityl, tetrahydropyranyl, tetrahydrofuranyl, allyl,fluoroacetyl, difluoroacetyl, trifluoroacetyl, chloroacetyl,dichloroacetyl, trichloroacetyl, bromoacetyl, dibromoacetyl,methoxyacetyl, ethoxyacetyl, phenoxyacetyl, benzoyl, benzyl,methoxymethyl or benzyloxycarbonyl group, with the proviso that R¹cannot be a group of the following formula: ##STR15## (Z being CHR⁴ orC═O, and R⁴ being a hydroxyl group which is not protected or protectedby t-butyldimethylsilyl, dimethylhexylsilyl, trimethylsilyl,triethylsilyl, tri(t-butyl) silyl, trityl, tetrahydropyranyl,tetrahydrofuranyl, allyl, fluoroacetyl, difluoroacetyl, trifluoroacetyl,chloroacetyl, dichloroacetyl, trichloroacetyl, bromoacetyl,dibromoacetyl, methoxyacetyl, ethoxyacetyl, phenoxyacetyl, benzoyl,benzyl, methoxymethyl or benzyloxycarbonyl group); R² represents ahydrogen atom or acyl group selected from the group consisting offormyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl,pivaloyl, hexanoyl, benzoyl, toluoyl, xyloyl groups, phenylacetyl,phenylpropionyl and phenylhexanoyl groups; W represents a hydrogen atomor alkanoyloxy group, selected from the group con2isting of linear orbranched alkanoyl groups having 1 to 6 atoms; Y represents a halogenatom, or sulfonyloxy group represented by the formula: --OSO₂ R³ whereinR³ represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, pentyl, 1-methybutyl, 2-methylbutyl, neopentyl,trifluoromethyl, 2-oxo-10-bornanyl, phenyl, p-methoxyphenyl,p-nitrophenyl, p-fluorophenyl, o,p-difluorophenyl, p-chlorophenyl,m-chlorophenyl, o-chlorophenyl, dichlorophenyl, p-bromophenyl,p-methylphenyl, m-methylphenyl, o,p-dimethylphenyl, m,p-dimethylphenyl,naphthyl, benzyl, p-nitrobenzyl, o,p-dinitrobenzyl, p-chlorobenzyl,m-chlorobenzyl, p-methylbenzyl, m-methylbenzyl, o-methylbenzyl,o,p-dimethylbenzyl, p-methoxybenzyl or p-fluorobenzyl groups; and brokenline "--------" represents a double bond when W is said hydrogen atomand a single bond when W is said slkanoyloxy group.
 4. A process forproducing a compound of the formula: ##STR16## wherein A represents acarbonyl group which is not protected or protected by dimethyiacetal,diethylacetal, diethylthioacetal, ethyieneacetal or propyleneacetal; Brepresents an aldehyde group which is not protected or protected bydimethylacetal, diethylacetal, diethylthioacetal, ethyleneacetal orpropyleneacetal; R¹ represents a hydroxyl group which is not protectedor protected by t-butyldimethylsilyl, dimethylhexylsilyl,trimethylsilyl, triethylsilyl, tri(t-butyl) silyl, trityl,tetrahydropyranyl, tetrahydrofuranyl, allyl, fluoroacetyl,difluoroacetyl, trifluoroacetyl, chloroacetyl, dichloroacetyl,trichloroacetyl, bromoacetyl, dibromoacetyl, methoxyacetyl,ethoxyacetyl, phenoxyacetyl, benzoyl, benzyl, methoxymethyl orbenzyloxycarbonyl group); R² represents a hydrogen atom or acyl groupselected from the group consisting of formyl, acetyl, propionyl,butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, benzoyl,toluoyl, xyloyl groups, phenylacetyl, phenylacetyl, phenylpropionyl andphenylhexanoyl groups; W and Y each represent a hydrogen atom and brokenline "-------" represents a single bond,by reducing a compound of,theabove-described formula wherein A, B, R¹ and R² are as defined above, Wrepresents a sulfonyloxy group represented by the formula: OSO² R³wherein R³ represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, pentyl, 1-methybutyl, 2-methylbutyl, neopentyl,trifluoromethyl, 2-oxo-10-bornanyl, phenyl, p-methoxyphenyl,p-nitrophenyl, p-fluorophenyl, o,p-difluorophenyl, p-chlorophenyl,m-chlorophenyl, o-chlorophenyl, o,p-dichlorophenyl, p-bromophenyl,p-methylphenyl, m-methylphenyl, o,p-dimethylphenyl, m,p-dimethylphenyl,naphthyl, benzyl, p-nitrobenzyl, o,p-dinitrobenzyl, p-chlorobenzyl,m-chlorobenzyl, p-methylbenzyl, m-methylbenzyl, o-methylbenzyl,o,p-dimethylbenzyl, p-methoxybenzyl or p-fluorobenzyl group; and Y.represents a halogen atom and broken line "-------" represents a singlebond under an alkaline condition.
 5. A process for producing a compoundof the formula: ##STR17## wherein A represents a carbonyl group which isnot protected or protected by dimethylacetal, diethylacetal,diethylthioacetal, ethyleneacetal or propyleneacetal; B represents analdehyde group which is not protected or protected by dimethylacetal,diethylacetal, diethylthioacetal, ethyleneacetal or propyleneacetal; R¹represents a hydroxyl group which is not protected or protected byt-butyldimethylsilyl, dimethylhexylsilyl, trimethylsilyl, triethylsilyl,tri(t-butyl)silyl, trityl, tetrahydropyranyl, tetrahydrofuranyl, allyl,fluoroacetyl, difluoroacetyl, trifluoroacetyl, chloroacetyl,dichloroacetyl, trichloroacetyl, bromoacetyl, dibromoacetyl,methoxyacetyl, ethoxyacetyl, phenoxyacetyl, benzoyl, benzyl,methoxymethyl or benzyloxycarbonyl group; R² represents a hydrogen atomor acyl group selected from the group consisting of formyl, acetyl,propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl,benzoyl, toluoyl, xyloyl groups, phenylacetyl, phenylacetyl,phenylpropionyl and phenylhexanoyl groups; W and Y each represent ahydrogen atom and broken line "-------" represents a single bond,whichcomprises the steps of reacting a compound of the above-describedformula wherein A, B, R¹ and R² are as defined above, W and Y eachrepresent a hydroxyl group and broken line "-------" represent a singlebond with a sulfonylating agent to form a compound of theabove-described formula wherein A, B, B¹ and B² are as defined above, Wand Y each represent sulfonyloxy group represented by the formula: OSO²R³ wherein R³ represents methyl, ethyl, propyl, isopropyl, butyl,isobutyl, tert-butyl, pentyl, 1-methybutyl, 2-methylbutyl, neopentyl,trifluoromethyl, 2-oxo-10-bornanyl, phenyl, p-methoxyphenyl,p-nitrophenyl, p-fluorophenyl, o,p-difluorophenyl, p-chlorophenyl,m-chlorophenyl, o-chlorophenyl, o,p-dichlorophenyl, p-bromophenyl,p-methylphenyl, m-methylphenyl, o,p-dimethylphenyl, m,p-dimethylphenyl,naphthyl, benzyl, p-nitrobenzyl, o,p-dinitrobenzyl, p-chlorobenzyl,m-chlorobenzyl, p-methylbenzyl, m-methylbenzyl, o-methylbenzyl,o,p-dimethylbenzyl, p-methoxybenzyl or p-fluorobenzyl group; and brokenline "-------" represents a single bond; reacting the resultant compoundwith a halogenating agent to form a compound of the above-describedformula wherein A, B, R¹ and R² are as defined above, W represents saidsulfonyloxy group, Y represents a halogen atom and broken line "-------"represents a single bond; and reducing the resultant compound under analkaline condition to form the product compound.
 6. A process forproducing 3,4'-dideoxymycaminosyltylonolide or a salt thereof whichcomprises steps of reacting a compound of the formula: ##STR18## whereinA represents a carbonyl group which is not protected or protected bydimethylacetal, diethylacetal, diethylthioacetal, ethyleneacetal orpropyleneacetal; B represents an aldehyde group which is not protectedor protected by dimethylacetal, diethylacetal, diethylthioacetal,ethyleneaoetal or propyleneacetal; R¹ represents a hydroxyl group whichis not protected or protected by t-butyldimethylsilyl,dimethylhexylsilyl, trimethylsilyl, triethylsilyl, tri(t-butyl)silyl,trityl, tetrahydropyranyl, tetrahydrofuranyl, allyl, fluoroacetyl,difluoroacetyl, trifluoroacetyl, chloroacetyl, dichloroacetyl,trichloroacetyl, bromoacetyl, dibromoacetyl, methoxyacetyl,ethoxyacetyl, phenoxyacetyl, benzoyl, benzyl, methoxymethyl orbenzyloxycarbonyl group); R² represents a hydrogen atom or acyl groupselected from the group consisting of formyl, acetyl, propionyl,butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, benzoyl,toluoyl, xyloyl groups, phenylacetyl, phenylacetyl, phenylpropionyl andphenylhexanoyl groups; W and Y each represent a hydrogen atom and brokenline "-------" represents a single bond,with a sulfonylating agent toform a compound of the above-described formula wherein A, B, R¹ and R²are as defined above, W and Y each represent a sulfonyloxy group,represented by the formula: OSO² R³ wherein R³ represents methyl, ethyl,propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, 1-methybutyl,2-methylbutyl, neopentyl, trifluoromethyl, 2-oxo-10-bornanyl, phenyl,p-methoxyphenyl, p-nitrophenyl, p-fluorophenyl, o,p-difluorophenyl,p-chlorophenyl, m-chlorophenyl, o-chlorophenyl, o,p-dichlorophenyl,p-bromophenyl, p-methylphenyl, m-methylphenyl, o,p-dimethylphenyl,m,p-dimethylphenyl, naphthyl, benzyl, p-nitrobenzyl, o,p-dinitrobenzyl,p-chlorobenzyl, m-chlorobenzyl, p-methylbenzyl, m-methylbenzyl,o-methylbenzyl, o,p-dimethylbenzyl, p-methoxybenzyl or p-fluorobenzylgroup; and broken line "-------" represents a single bond; reacting theresultant compound with a halogenating agent to form a compound of theabove-described formula wherein A, B, R¹ and R² are as defined above, Wrepresents said sulfonyloxy group, Y represents a halogen atom andbroken line "-------" represents a single bond; reducing the resultantcompound under an alkaline condition to form the compound of theabove-described formula wherein A, B, R¹ and R² are as defined above, wand Y each represent a hydrogen atom and broken line "--------"represents a single bond; and removing the protecting group from thethus-obtained compound.
 7. The process of claim 5 wherein saidsulfonylating agent is methanesulfonyl chloride or benzylsulfonylchloride.
 8. The process of claim 6 wherein said sulfonylating agent ismethanesulfonyl chloride or benzylsulfonyl chloride.
 9. The process ofclaim 5 wherein said halogenating agent is sodium iodide.
 10. Theprocess of claim 6 wherein said halogenating agent is sodium iodide.